Pyridin-2-yl-amino-1, 2, 4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus

ABSTRACT

Provided are compounds of Formula (I): wherein R 2 , R 3 , R 13 , L and D 2  are as defined in the specification, which are useful in the treatment and/or prevention of diseases or disorders mediated by deficient levels of glucokinase activity or which can be treated by activating glucokinase including, but not limited to, diabetes mellitus, impaired glucose tolerance, IFG (impaired fasting glucose) and IFG (impaired fasting glycemia), as well as other diseases and disorders such as those discussed herein.

This application claims priority to U.S. Provisional Application No.60/974,225, filed on Sep. 21, 2007.

The present invention relates to novel compounds, to pharmaceuticalcompositions comprising the compounds, to a process for making thecompounds and to the use of the compounds in therapy. More particularly,it relates to certain glucokinase activators useful in the treatment ofdiseases and disorders that would benefit from activation ofglucokinase.

Glucokinase (hexokinase IV or D) is a glycolytic enzyme that plays animportant role in blood sugar regulation related to the glucoseutilization and metabolism in the liver and pancreatic beta cells.Serving as a glucose sensor, glucokinase controls plasma glucose levels.Glucokinase plays a dual role in reducing plasma glucose levels:glucose-mediated activation of the enzyme in hepatocytes facilitateshepatic glucose update and glycogen synthesis, while that in pancreaticbeta cells ultimately induces insulin secretion. Both of these effectsin turn reduce plasma glucose levels.

Clinical evidence has shown that glucokinase variants with decreased andincreased activities are associated with diabetes of the young type(MODY2) and persistent hyperinsulinemic hypoglycemia of infancy (PHHI),respectively. Also, non-insulin dependent diabetes mellitus (NIDDM)patients have been reported to have inappropriately low glucokinaseactivity. Furthermore, overexpression of glucokinase in dietary orgenetic animal models of diabetes either prevents, ameliorates, orreverses the progress of pathological symptoms in the disease. For thesereasons, compounds that activate glucokinase have been sought by thepharmaceutical industry.

International patent application, Publication No. WO 2007/053345, whichwas published on May 10, 2007, discloses as glucokinase activatorscertain 2-aminopyridine derivatives bearing at the 3-position amethyleneoxy-linked aromatic group and on the amino group a heteroarylring, such as thiazolyl or 1,2,4-thiadiazolyl.

It has now been found that 2-aminopyridine derivatives bearing at the3-position an oxy- or thio-linked aromatic group and on the amino groupa thiazolyl or 1,2,4-thiadiazolyl substituted by a polyhydroxyalkyl orpolyhydroxycycloalkyl group at the 4 or 3 position of the thiazole orthiadiazole ring, respectively are glucokinase activators. Certain ofthese compounds have been found to have an outstanding combination ofproperties that especially adapts them for oral use with controlledplasma glucose levels.

According to one aspect, the present invention provides a compound ofgeneral Formula I

or a salt thereof, wherein:

R¹³ is a polyhydroxy-(2-6C) alkyl, methoxy(polyhydroxy-(3-6C) alkyl) orpolyhydroxy-(5-6C)cycloalkyl;

L is O or S;

D² is N or CH;

R² is Ar¹, hetAr¹, hetAr², or hetAr³;

Ar¹ is phenyl or naphthyl, each of which is optionally substituted withone or more groups independently selected from (1-6C)alkyl, F, Br, CF₃,OH, CN, SO₂Me, C(═O)NH(1-3C alkyl)N(alkyl)₂ and C(═C)NH(1-3Calkyl)hetCyc¹;

hetAr¹ is a 5-6 membered heteroaryl group having 1-3 ring nitrogen atomsand optionally substituted with one or more groups independentlyselected from (1-6C alkyl), Cl, CF₃ and (1-6C alkyl)OH;

hetAr² is a partially unsaturated 5,6 or 6,6 bicyclic heteroaryl ringsystem having 1-2 ring nitrogen atoms and optionally having a ringoxygen atom;

hetAr³ is a 9-10 membered bicyclic heteroaryl ring having 1-3 ringnitrogen atoms;

R³ is Cl, Br, CF₃, aryl, hetAr^(a), SR⁶ or OR⁶;

hetAr^(a) is a 6-membered heteroaryl having 1-2 ring nitrogen atoms;

R⁶ is Ar², hetAr⁴, (1-6C alkyl), -(1-6C alkyl)OH, polyhydroxy(1-6Calkyl), —CH(R⁹)—Ar³, —CH(R¹⁰)-hetAr⁵, hetAr⁶, (5-6C)cycloalkylsubstituted with 1 to 4 OH, (1-3 C alkoxy)(1-6C alkyl), orcyclopropyl(1-6C alkyl);

Ar² is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, F, Br, Cl, CF₃, CN, OH, O-(1-6Calkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl)₂and C(═O)NH(1-3C alkyl)hetCyc²;

hetAr⁴ is a 5-6-membered heteroaryl ring having 1-3 nitrogen atoms andoptionally substituted with one or more groups independently selectionsfrom (1-6C)alkyl, F, Br, Cl, CF₃, CN, OH, O-(1-6C alkyl), C(═O)OH,C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl)₂ and C(═O)NH(1-3Calkyl)hetCyc²;

Ar³ is phenyl optionally substituted with one or more groupsindependently selected from F, Cl, Br, and (1-6C)alkyl;

hetAr⁵ is a 5-6-membered heteroaryl having 1-2 ring nitrogen atoms;

hetAr⁶ is a 9-10 membered bicyclic heteroaromatic ring having 2-3heteroatoms independently selected from N, S, O (provided the ring doesnot contain an O—O bond) which is optionally substituted with one ormore groups independently selected from (1-6C)alkyl, F, Br, Cl, CF₃, CN,OH, —O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl) and C(═O)NH(1-3Calkyl)N(1-3Calkyl)₂;

R⁹ and R¹⁰ are independently hydrogen, (1-6C)alkyl, (1-6C)alkylOH, orCF₃; and

hetCyc¹ and hetCyc² are independently a 5-7 membered heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O.

Compounds of Formula I include compounds, including salts thereof,wherein:

R¹³ is a polyhydroxy-(2-6C) alkyl or polyhydroxy-(5-6C)cycloalkyl;

L is O or S;

D² is N or CH;

R² is Ar¹, hetAr¹, hetAr², or hetAr³;

Ar¹ is phenyl or naphthyl, each of which is optionally substituted withone or more groups independently selected from (1-6C)alkyl, F, Br, CF₃,OH, CN, SO₂Me, C(═O)NH(1-3C alkyl)N(alkyl)₂ and C(═O)NH(1-3Calkyl)hetCyc¹;

hetAr¹ is a 5-6 membered heteroaryl group having 1-3 ring nitrogen atomsand optionally substituted with one or more groups independentlyselected from (1-6C alkyl), Cl, CF₃ and (1-6C alkyl)OH;

hetAr² is a partially unsaturated 5,6 or 6,6 bicyclic heteroaryl ringsystem having 1-2 ring nitrogen atoms and optionally having a ringoxygen atom;

hetAr³ is 9-10 membered bicyclic heteroaryl ring having 1-3 ringnitrogen atoms;

R³ is Cl, Br, CF₃, aryl, hetAr^(a), SR⁶ or OR⁶;

hetAr^(a) is a 6-membered heteroaryl having 1-2 ring nitrogen atoms,

R⁶ is Ar², hetAr⁴, (1-6C alkyl), -(1-6C alkyl)OH, polyhydroxy(1-6Calkyl), —CH(R⁹)—Ar³, —CH(R¹⁰)-hetAr⁵, hetAr⁶ or (5-6C)cycloalkylsubstituted with 1 to 4 OH;

Ar² is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, F, Br, Cl, CF₃, CN, OH, O-(1-6Calkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl)₂and C(═C alkyl)hetCyc²;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 nitrogen atoms andoptionally substituted with one or more groups independently selectedfrom (1-6C)alkyl, F, Br, Cl, CF₃, CN, OH, O-(1-6C alkyl), C(═O)OH,C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl)₂ and C(═O)NH(1-3Calkyl)hetCyc²;

Ar³ is phenyl optionally substituted with one or more groupsindependently selected from F, Cl, Br, and (1-6C)alkyl;

hetAr⁵ is a 5-6-membered heteroaryl having 1-2 ring nitrogen atoms;

hetAr⁶ is a 9-10 membered bicyclic heteroaromatic ring having 2-3heteroatoms independently selected from N, S and O (provided the ringdoes not contain an O—O bond) which is optionally substituted with oneor more groups independently selected from (1-6C)alkyl, F, Br, Cl, CF₃,CN, OH, —O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl) and C(═O)NH(1-3Calkyl)N(1-3Calkyl)₂;

R⁹ and R¹⁰ are independently hydrogen, (1-6C)alkyl, (1-6C)alkylOH, orCF₃; and

hetCyc¹ and hetCyc² are independently a 5-7 membered heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O.

The terms “(1-6C)alkyl,” “(1-3C)alkyl,” and “(2-6C)alkyl” as used hereinrefer to a saturated linear or branched-chain monovalent hydrocarbonradical of one to six, one to three, or two to six carbon atoms,respectively. Examples include but are not limited to, methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl,2-methyl-2-propyl, 2,2-dimethylpropyl, 1-pentyl, 2-pentyl, 3-pentyl,2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl,1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl,2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

In one embodiment of Formula I, R¹³ is a polyhydroxy-(2-6C) alkyl. Forexample, in one embodiment R¹³ is a (2-6C)alkyl group substituted withtwo to three hydroxy groups, for example two hydroxy groups. Examplesinclude ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,1,2-dimethylbutyl, 2,3-dimethylbutyl, tert-butyl, pentyl, neopentyl andisopentyl groups substituted with 2-3 hydroxy groups, for example 2hydroxy groups.

Particular values for R¹³ include the structures:

In certain embodiments, R¹³ is a methoxy(polyhydroxy-(3-6C)alkyl). Incertain embodiments, R¹³ is a methoxy(dihydroxy(3-6C)alkyl). An exampleof a particular value for R¹³ is the structure

In certain embodiments of Formula I, the alpha carbon is in the Sconfiguration. In other embodiments, the alpha carbon is in the Rconfiguration.

In certain embodiments of Formula I, R¹³ is selected from thestructures:

In particular embodiments, R¹³ is 1,2-dihydroxyethyl.

In certain embodiments, R¹³ is a polyhydroxy-(2-6C) alkyl group in whichone of the hydroxy groups is on the alpha carbon. In one embodiment, thealpha carbon is in the S configuration. In other embodiments, the alphacarbon is in the R configuration. A particular value of R¹³ is(S)-1,2-dihydroxyethyl or (R)-1,2-dihydroxyethyl, which can berepresented, respectively, by the structures:

In one embodiment of Formula I, R¹³ is a polyhydroxy-(5-6C)cycloalkylgroup. For example, in certain embodiments, R¹³ is cyclopentyl orcyclohexyl substituted with 2-3 hydroxyl groups, for example 2 hydroxylgroups. Particular values for R¹³ include the structures:

In certain embodiments, R² is Ar¹. In certain embodiments, Ar¹ isoptionally substituted with one or more groups independently selectedfrom (1-6C)alkyl, F, Br, Cl, CF₃, CN, OH, —O-(1-6C alkyl), C(═O)OH,C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl)₂ and C(═O)NH(1-3Calkyl)hetCyc¹. In certain embodiments, Ar¹ is optionally substitutedwith one or more groups independently selected from C₁-C₆ alkyl, F, Brand CF₃.

In certain embodiments, Ar¹ is phenyl. In other embodiments, Ar¹ isnaphthyl. In certain embodiments, Ar¹ is optionally substituted with oneor more groups independently selected from (1-6C)alkyl, F, Br, CF₃, CN,SO₂Me and C(═O)NHCH₂CH₂NMe₂.

Exemplary embodiments of R² when represented by Ar¹ include thestructures:

In one embodiment, R² is hetAr¹.

In one embodiment, hetAr¹ is unsubstituted. In another embodiment,hetAr¹ is substituted with one or more groups independently selectedfrom (1-6C alkyl), Cl, CF₃ and (1-5C alkyl)OH.

In one embodiment, hetAr¹ is an optionally substituted 6-memberedheteroaryl group having 1-2 ring nitrogen atoms. Examples of hetAr¹include unsubstituted or substituted pyridyl, pyrazinyl and pyridazinylgroups. In certain embodiment, the 6-membered hetAr¹ is unsubstituted orsubstituted with one or more groups independently selected from methyl,ethyl, isopropyl, chloro, CF₃, CH₂OH, and CH₂CH₂OH. Examples includepyridyl, methylpyridyl, dimethylpyridyl, ethylpyridyl, isopropylpyridyl,chloropyridyl, trifluoromethylpyridyl, hydroxymethylpyridyl,hydroxyethylpyridyl, methylpyrazinyl and methylpyridazinyl.

In another embodiment, hetAr¹ is an optionally substituted 5-memberedheteroaryl group having 1-3 ring nitrogen atoms. Examples includepyrazolyl, imidazolyl and triazolyl groups. In certain embodiments, the5-membered hetAr¹ is unsubstituted or substituted with one or moregroups independently selected from (1-6C alkyl), CF₃, Cl, or (1-3Calkyl)OH, for example one or more groups independently selected frommethyl, ethyl, isopropyl, CF₃, CH₂OH and CH₂CH₂OH. Examples includepyrazolyl, methylpyrazolyl, dimethylpyrazolyl, imidazolyl,methylimidazolyl, dimethylimidazolyl, hydroxyethylpyrazolyl, anddimethylhydroxyethylpyrazolyl groups.

Further examples of hetAr¹ include ethylpyrazolyl and trimethylpyrazolylgroups.

Particular values for R² when represented by hetAr¹ include thestructures:

Additional values for R² when represented by hetAr¹ include thestructures:

In certain embodiments of Formula I, R² is a pryidyl or pyrazolyl ringsubstituted with one or more groups independently selected from(1-6C)alkyl. In certain embodiments, R² is pyrid-3-yl, pyrazol-4-yl orpyrazol-5-yl substituted with one or more groups independently selectedfrom methyl and ethyl. Particular values for R² include the structures:

In certain embodiments, R² is hetAr² wherein herAr² is a partiallyunsaturated 5,5, 5,6 or 6,6 bicyclic ring system having 1-2 ringnitrogen atoms and optionally having a ring oxygen atom. Examples ofsuch ring systems include 5,6,7,8-tetrahydroquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,6,7-dihydro-5H-cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[b]pyridinyl,6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,2,3-dihydrofuro[2,3-c]pyridinyl, 2,3-dihydrofuro[3,2-b]pyridinyl,2,3-dihydrofuro[3,2-c]pyridinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl,3,4-dihydro-2H-pyrano[2,3-c]pyridinyl,3,4-dihydro-2H-pyrano[3,2-c]pyridinyl, and3,4-dihydro-2H-pyrano[3,2-b]pyridinyl.

Particular examples of R² when represented by hetAr² include thestructures:

In certain embodiments, R² is hetAr³ wherein hetAr³ is a 9-10 memberedbicyclic heteroaryl ring having 1-3 ring nitrogen atoms. Examples ofsuch ring systems include [1,2,4]triazolo[4,3-a]pyridinyl and[1,2,4]triazolo[1,5-a]pyridinyl rings.

Particular values for R² when represented by hetAr³ include thestructures:

Referring to the R³ group of Formula I, in certain embodiments R³ isSR⁶.

In certain embodiment, R³ is SR⁶ and R⁶ is Ar². In certain embodiments,Ar² is unsubstituted. In other embodiments, Ar² is substituted with oneor more groups independently selected from (1-6C)alkyl, F, Br, Cl, CF₃,CN, OH, —O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3Calkyl)N(1-3Calkyl)₂ and C(═O)NH(1-3C alkyl)hetCyc². In certainembodiments, Ar² is substituted with one or two groups independentlyselected from Cl, (1-6C)alkyl, CN, CF₃, and —O(C₁-C₆ alkyl).

In a certain embodiment, Ar² is an optionally substituted phenyl.

Exemplary embodiment of R³ when represented by —S—Ar² includephenylthio, (chlorophenyl)thio, (fluorophenyl)thio, (methylphenyl)thio,(trifluromethylphenyl)thio, (dimethylphenyl)thio,(cyanotrifluoromethylphenyl)thio, (cyanophenyl)thio, and(methoxyphenyl)thio.

Particular values of R³ when represented by —S—Ar² include thestructures:

In another embodiment of Formula I, R³ is SR⁶ wherein R⁶ is hetAr⁴, andhetAr⁴ is an optionally substituted 5-6 membered heteroaryl ring having1-3 ring nitrogen atoms. Examples include optionally substitutedpyridyl, pyrimidyl, pyrrolyl, imidazolyl and triazolyl rings. In certainembodiments, hetAr⁴ is unsubstituted or substituted with one or moregroups independently selected from (1-6C)alkyl, F, Br, Cl, CF₃, CN, OH,—O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3Calkyl)N(1-3Calkyl)₂ and C(═O)NH(1-3C alkyl)hetCyc². In particularembodiments, herAr⁴ is substituted with one or more (1-6C) alkyl groups,for example one or more methyl groups.

Particular values for R³ when represented by —S-hetAr⁴ include thestructures:

An additional value of —S-hetAr⁴ includes the structure:

Particular mention is made of —S-hetAr⁴ groups selected from—S-(methylpyridyl), —S-(dimethylpyridyl), —S-(methylimidazolyl), and—S-(methyltriazolyl).

In another embodiment of Formula I, R³ is SR⁶ wherein R⁶ is (1-6Calkyl)OH or polyhydroxy(1-6C alkyl). Examples of polyhydroxy(1-6C alkyl)groups include 1-6C alkyl groups substituted with 2 to 3 hydroxy groups.Particular values include the structures:

In certain embodiments, R³ is SR⁶ where R⁶ is (5-6C)cycloalkylsubstituted with 1-4 OH groups, for example 1-2 OH groups.

In another embodiment of Formula I, R³ is SR⁶ wherein R⁶ is CH(R⁹)—Ar³.In certain embodiments, R⁹ is H. In certain embodiments, R⁹ is(1-6C)alkyl, for example (1-3C alkyl), for example methyl. In certainembodiments, R⁹ is CH₂OH. In certain embodiments, Ar³ is anunsubstituted phenyl. In other embodiments, Ar³ is phenyl which issubstituted with one or more groups independently selected from F, Cl,Br, and (1-6C)alkyl. Particular values for R³ when represented byS—(CH(R⁹)—Ar³ include the structures:

In another embodiment of Formula I, R³ is SR⁶ where in R⁶ isCH(R¹⁰)-hetAr⁵. In certain embodiments, R¹⁰ is H. In certainembodiments, R¹⁰ is (1-6C)alkyl, for example (1-3C alkyl), for examplemethyl. In certain embodiments, R¹⁰ is CH₂OH. In certain embodiments,hetAr⁵ is pyridyl. In other embodiments, hetAr⁵ is pyrimidyl.

Particular values for R³ when represented by S—CH(R¹⁰)-hetAr⁵ includethe structures:

In certain embodiments of Formula I, R³ is SR⁶ wherein R⁶ is hetAr⁶ andhetAr⁶ is a 9-10 membered bicyclic heteroaromatic ring having 2-3heteroatoms independently selected from N, S and O (provided the ringdoes not contain an O—O bond). Examples include 5,5 and 5,6 fused ringsystems. Particular examples include thienopyridyl, thienopyrimidyl,isoxazolopyridyl, pyrazolopyrimidyl and imidazopyridine rings.

In certain embodiments, hetAr⁶ is unsubstituted. In certain embodiments,hetAr⁶ is substituted with one or more groups independently selectedfrom (1-6C)alkyl, F, Br, Cl, CF₃, CN, OH, —O-(1-6C alkyl), C(═O)OH,C(═O)O(1-6C alkyl) and C(═C)NH(1-3C alkyl)N(1-3Calkyl)₂.

In particular embodiments, herAr⁶ is optionally substituted with one ortwo groups independently selected from Br, Cl, C₁-C₆ alkyl, and O(1-6alkyl). Particular substituents include Br, Cl, Me, and OMe.

Particular values of R³ when represented by S-hetAr⁶ include thestructures:

In certain embodiments, R³ is SR⁶ wherein R⁶ is (1-6C)alkyl. Aparticular value for R³ when represented by —S(1-6C alkyl) is SMe.

In certain embodiments, R³ is SR⁶ wherein R⁶ is (1-3C alkoxy)(1-6Calkyl). Examples of R⁶ include methoxy(1-6C alkyl) groups. Particularvalues for SR⁶ include —S(CH₂CH₂)OMe and —S(CH₂CH₂CH₂)OMe.

In certain embodiments, R³ is SR⁶ wherein R⁶ is cyclopropyl(1-6C alkyl).A particular value for SR⁶ is —SCH₂(cyclopropyl).

In certain embodiments, R³ is SR⁶ wherein R⁶ is selected from (1-3Calkoxy)(1-6C alkyl), cyclopropyl(1-6C alkyl), and pyridyl optionallysubstituted with one or more groups independently selected from (1-6Calkyl).

In certain embodiments, R³ is SR⁶ wherein R⁶ is selected frommethoxy(2-3C alkyl), cyclopropylmethyl, or pyridyl-2-yl optionallysubstituted with (1-6C alkyl).

Particular values for R⁶ of Formula I include the structures:

In certain embodiments, R³ is aryl. In a particular embodiment, R³ isphenyl.

In certain embodiments, R³ is hetAr^(a). In certain embodiments, R³ ispyridyl or pyrimidyl. In a particular embodiment, R³ is 2-pyridyl.

In certain embodiments, R³ is Cl.

In certain embodiments, R³ is Br.

In certain embodiments, R³ is CF₃.

In certain embodiments, R³ is OR⁶. In one embodiment, R⁶ is anoptionally substituted Ar². In other embodiments, R⁶ is an optionallysubstituted hetAr⁴. In certain embodiments, hetAr⁴ is a 6-memberedheteroaryl having 1-2 ring nitrogens, for example pyridyl. Examples ofR⁶ groups include phenyl, chlorophenyl, pyridyl and methylpyridyl.Particular values of R³ when represented by OR⁶ include the structures:

In certain embodiments, R³ is OR⁶ where R⁶ is hetAr⁴.

In certain embodiments, R³ is OR⁶ where R⁶ is (1-6C alkyl).

In certain embodiments, R³ is OR⁶ where R⁶ is -(1-6C alkyl)OH.

In certain embodiments, R³ is OR⁶ where R⁶ is polyhydroxy(1-6C alkyl).

In certain embodiments, R³ is OR⁶ where R⁶ is —CH(R⁹)—Ar³.

In certain embodiments, R³ is OR⁶ where R⁶ is —CH(R¹⁰)-hetAr⁵.

In certain embodiments, R³ is OR⁶ where R⁶ is hetAr⁶.

In certain embodiments, R³ is OR⁶ where R⁶ is (5-6C)cycloalkylsubstituted with 1-4 OH.

In one embodiment of Formula I, D² is CH.

In one embodiment of Formula I, D² is N.

In one embodiment of Formula I, L is O.

In one embodiment of Formula I, L is S.

The compounds of Formula I also include compounds of Formula Ia

and salts thereof, wherein:

R¹³ is a dihydroxy-(2-6C) alkyl or dihydroxy-(5-6C)cycloalkyl;

D² is N or CH;

R² is hetAr¹, hetAr², or hetAr³;

hetAr¹ is a 5-6 membered heteroaryl group having 1-3 ring nitrogen atomsand optionally substituted with one or more groups independentlyselected from (1-6C alkyl), Cl, CF₃ and (1-6C alkyl)OH;

hetAr² is a partially unsaturated 5,5, 5,6 or 6,6 bicyclic ring systemhaving 1-2 ring nitrogen atoms and optionally having a ring oxygen atom;

hetAr³ is a 9-10 membered bicyclic heteroaryl ring having 1-3 ringnitrogen atoms;

R³ is Cl, Br, CF₃, aryl, hetAr^(a), SR⁶ or OR⁶;

hetAr^(a) is a 6-membered heteroaryl having 1-2 ring nitrogen atoms;

R⁶ is Ar², hetAr⁴, (1-6C alkyl)OH, CH(R⁹)—Ar³, or CH(R¹⁰)-hetAr⁵;

Ar² is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, F, Br, Cl, CF₃, CN, OH, O-(1-6Calkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl)₂and C(═O)NH(1-3C alkyl)hetCyc²;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 nitrogen atoms andoptionally substituted with one or more groups independently selectedfrom (1-6C)alkyl, F, Br, Cl, CF₃, CN, OH, O-(1-6C alkyl), C(═O)OH,C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl)₂ and C(═O)NH(1-3Calkyl)hetCyc²;

Ar³ is phenyl optionally substituted with one or more groupsindependently selected from F, Cl, Br, and (1-6C)alkyl;

hetAr⁵ is a 6-membered heteroaryl having 1-2 ring nitrogen atoms; and

R⁹ and R¹⁰ are independently hydrogen, (1-6C)alkyl, or CH₂OH.

In certain embodiments of Formula Ia, R² is hetAr¹.

In certain embodiments of Formula Ia, R² is hetAr².

In certain embodiments of Formula Ia, R² is hetAr³.

In certain embodiments of Formula Ia, R³ is Cl.

In certain embodiments of Formula Ia, R³ is Br.

In certain embodiments of Formula Ia, R³ is CF₃.

In certain embodiments of Formula Ia, R³ is aryl.

In certain embodiments of Formula Ia, R³ is hetAr^(a).

In certain embodiments of Formula Ia, R³ is SR⁶.

In certain embodiments of Formula Ia, R³ is OR⁶.

The compounds of Formula I also include compounds of Formula Ib

and salts thereof wherein:

R¹³ is 1,2-dihydroxyethyl;

D² is N or CH;

R² is phenyl, pyridyl or pyrazolyl, each of which is optionallysubstituted with one or more (1-6C)alkyl groups; and

R⁶ is phenyl, pyridyl or (1-6C alkyl)OH, wherein said phenyl and pyridylare optionally substituted with one or more (1-6C)alkyl groups.

It has been found that compounds of Formula Ib have improvedpharmacokinetic properties. For example, certain compounds of Formula Ibhave been found to have increased oral bioavailability, increasedexposure (i.e., increased blood levels over time), and/or lowerclearance. In addition, certain compounds of Formula Ib have been foundto have increased aqueous solubility.

In certain embodiments of Formula Ib, R¹³ is (S)-1,2-dihydroxyethyl.

In certain embodiments of Formula Ib, R¹³ is (R)-1,2-dihydroxyethyl.

In certain embodiments of Formula Ib, D² is N.

In certain embodiments of Formula Ib, D² is CH.

In certain embodiments of Formula Ib, R² is phenyl.

In certain embodiments of Formula Ib, R² is pyridyl. In certainembodiments, the pyridyl group is substituted with one or more(1-6C)alkyl groups, for example one or more methyl groups, for exampleone methyl group. In particular embodiments of Formula Ib, R² isselected from the structures:

In certain embodiments of Formula Ib, R² is pyrazolyl which isoptionally substituted with one or more (1-6C)alkyl groups. In certainembodiments, R² is 1H-pyrazolyl. In particular embodiments, R² is1H-pyrazol-4-yl. In certain embodiments, the pyrazolyl group issubstituted with one or more (1-3C)alkyl groups, for example one or moremethyl groups. In particular embodiments of Formula Ib, R² is selectedfrom the structures:

In certain embodiments of Formula Ib, R⁶ is phenyl.

In certain embodiments of Formula Ib, R⁶ is pyridyl. In certainembodiments, R⁶ is 3-pyridyl. In certain embodiments, the pyridyl issubstituted with a (1-6C)alkyl group, for example a methyl group.Particular values for R⁶ include pyrid-3-yl and 2-methylpyrid-3-yl.

In certain embodiments of Formula Ib, R⁶ is (1-3C alkyl)OH. A particularvalue is —CH₂CH₂OH.

In a particular embodiment of Formula Ib:

D² is N;

R² is pyridyl or pyrazolyl, each of which is optionally substituted withone or more methyl groups; and

R³ is pyridyl optionally substituted with one or more methyl groups.

Formula I also includes a compound of the general Formula Ic:

or a pharmaceutically acceptable salt thereof, wherein:

R¹³ is dihydroxy(2-6C)alkyl or methoxy(dihydroxy(3-6C)alkyl);

R² is a pyridyl or pyrazolyl ring, each of which is optionallysubstituted with one or more groups independently selected from(1-6C)alkyl; and

R⁶ is (1-3C alkoxy)(1-6C alkyl)-, cyclopropyl(1-6 C alkyl)-, or pyridyloptionally substituted with one or more groups independently selectedfrom (1-6C alkyl).

In one embodiment of Formula Ic, R¹³ is dihydroxy(2-4C)alkyl ormethoxy(dihydroxy(3-4C)alkyl).

In one embodiment of Formula Ic, R¹³ is a 1,2-dihydroxy(2-4C alkyl) or amethoxy(1,2-dihydroxy(3-4C)alkyl), such as 3-methoxy-1,2-dihydroxy(3-4Calkyl). In one embodiment of Formula Ic, the alpha carbon of the R¹³group is in the S configuration. In another embodiment, the alpha carbonof the R¹³ group is in the R configuration.

In one embodiment of Formula Ic, R¹³ is selected from the structures:

Particular values of R¹³ for Formula Ic can be represented by thestructures:

In certain embodiments of Formula Ic, R² is pyrid-3-yl, pyrazol-4-yl orpyrazol-5-yl, each of which is optionally substituted with one or moregroups independently selected from (1-6C alkyl), for example one or moregroups independently selected from methyl and ethyl. Particular valuesfor R² include the structures:

In one embodiment of Formula Ic, R⁶ is (1-3C alkoxy)(1-6C alkyl). In oneembodiment, R⁶ is CH₃O-(2-3C alkyl)-. Particular values of R⁶ forFormula Ic include the structures:

In one embodiment of Formula Ic, R⁶ is cyclopropyl(1-6 C alkyl)-. In aparticular embodiment, R⁶ is cyclopropylmethyl.

In one embodiment of Formula Ic, R⁶ is pyridyl optionally substitutedwith one or more groups independently selected from (1-6C alkyl). In oneembodiment, R⁶ is pyridyl-2-yl optionally substituted with one or moregroups independently selected from (1-6C alkyl), for example one or moregroups independently selected from methyl or ethyl. Particular valuesfor R⁶ of Formula Ic include the structures:

Formula I also includes a compound of the general Formula Id:

or a pharmaceutically acceptable salt thereof, wherein:

R¹³ is a 1,2-dihydroxy(2-6C)alkyl or amethoxy(1,2-dihydroxy(3-6C)alkyl);

R² is pyrid-3-yl, pyrazol-4-yl or pyrazol-5-yl, each of which isoptionally substituted with one or more groups independently selectedfrom (1-6C)alkyl; and

R⁶ is methoxy(2-3C alkyl), cyclopropylmethyl, or pyridyl-2-yl optionallysubstituted with (1-6C alkyl).

In one embodiment of Formula Id, the alpha carbon of the R¹³ group is inthe S configuration. In another embodiment, the alpha carbon of the R¹³group is in the R configuration.

In one embodiment of Formula Id, R¹³ is a 1,2-dihydroxy(2-4C)alkyl or amethoxy(1,2-dihydroxy(3-4C)alkyl), such as 3-methoxy-1,2-dihydroxy(3-4Calkyl).

In one embodiment of Formula Id, R¹³ is selected from the structures:

Particular values of R¹³ for Formula Id can be represented by thestructures:

In certain embodiments of Formula Id, R² is optionally substituted withone to three groups independently selected from (1-6C alkyl), forexample one to three groups independently selected from methyl andethyl. Particular values for R² include the structures:

In certain embodiment of Formula Id, R⁶ is methoxy(2-3C alkyl).Particular values include the structures:

In certain embodiments of Formula Id, R⁶ is cyclopropylmethyl.

In certain embodiments of Formula Id, R⁶ is pyridyl-2-yl optionallysubstituted with (1-6C alkyl), for example methyl or ethyl. Particularvalues for R⁶ of Formula Id include the structures:

It has been found that compounds of Formulas Ic and Id have particularlyunexpected and desirable properties. For example, the compounds havesufficient solubility, including at low pH, to have dose proportionalPK. Compounds of Formulas Ic and Id also have superior activity in thepresence of plasma proteins (i.e., in the presence of 4% HSA) whentested in the assay described in Example A.

The compounds of Formulas Ic and Id also unexpectedly have low clearancevia conjugation reactions. The main course of clearance of compounds ofFormulas Ic and Id is via hepatic oxidation of the 5-SR⁶ moiety and notconjugation to and/or oxidation of the diol moiety. This propertydiminishes the likelihood of saturation of a clearance mechanism;allowing good predictability of blood levels of the active compound andcontributing to dose proportional PK.

In addition, the compounds of Formulas Ic and Id unexpectedly achieve ahigh oral AUC (area under the plasma drug concentration-time curve aftera low oral dose), which results in a greater amount of the compoundwhich is available for binding to the glucokinase enzyme. Together withthe linear and dose proportional PK, this allows the therapeuticconcentrations of the compound to be reached in a predictable manner.

The dose proportionality and high exposure of compounds of Formulas Icand Id afford pharmacokinetic parameters that won't change whendifferent doses are administered or when the drug is given throughdifferent routes of administration or as single or multiple doses. As aresult, patients are less likely to be overdosed when doses are slightlyincreased. In addition, lower doses will be needed to achieve thetherapeutic efficacy.

In contrast, drugs with nonlinearity may have decreased oralbioavailability due to several possible reasons, including drugconcentration approaching the drug's solubility limit in the GI tract,or saturatable transport system for absorption or increased oralbioavailability due to saturatable metabolism at high concentrations.

Particular examples of compounds of Formulas Ic and Id are provided inTable 1, which also includes relative values for the oral AUC (at 10mg/kg) when tested in the assay described in Example B. The compounds inTable 1 were found to have an EC₅₀ value less than 1 μM when tested in4% HSA according to the assay described in Example A.

Particular examples of compounds of Formulas Ic and Id are provided inTable 1, which also provides relative values for the oral AUC (at 10mg/kg) when tested in the assay described in Example B. The compounds inTable 1 were found to have an EC₅₀ value less than 1 μM when tested in4% HSA according to the assay described in Example A.

TABLE 1 Example # Structure AUC indicator* 134

+++ 135

++ 136

+++ 137

++ 138

+ 139

++++ 140

++++ 141

+ 142

+ 143

++++ 144

++ 145

++ 146

+++ 147

+ 148

+ 149

++ 150

+++ 151

++++ *Indicator: + AUC = 1-5 μg*hr/mL ++ AUC = 5-10 μg*hr/mL +++ AUC =10-20 μg*hr/mL ++++ AUC = >20 μg*hr/mL

It will be appreciated that certain compounds according to the inventionmay contain one or more centers of asymmetry and may therefore beprepared and isolated in a mixture of isomers such as a racemic mixture,or in an enantiomerically pure form.

It will further be appreciated that the compounds of Formula I or theirsalts may be isolated in the form of solvates, and accordingly that anysuch solvate is included within the scope of the present invention.

The compounds of Formula I include pharmaceutically acceptable saltsthereof. In addition, the compounds of Formula I also include othersalts of such compounds which are not necessarily pharmaceuticallyacceptable salts, and which may be useful as intermediates for preparingand/or purifying compounds of Formula I and/or for separatingenantiomers of compounds of Formula I.

Compounds of this invention may be synthesized by synthetic routes thatinclude processes analogous to those well known in the chemical arts,particularly in light of the description contained herein. The startingmaterials are generally available from commercial sources such asAldrich Chemicals (Milwaukee, Wis.) or are readily prepared usingmethods well known to those skilled in the art (e.g., prepared bymethods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.), orBeilsteins Handbuch der organischen Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including supplements).

For illustrative purposes, Schemes A-S show general methods forpreparing the compounds of the present invention as well as keyintermediates. For a more detailed description of the individualreaction steps, see the Examples section below.

Scheme A shows a method of preparing compounds (3A) of Formula I. Toprepare compound (3A), a 2-aminoheterocycle (1) is reacted withbenzoylisothiocyanate to afford a benzoylthiourea intermediate, which ishydrolyzed to the thiourea (2) with a base such as, but not limited to,potassium carbonate in a suitable solvent such as, but not limited to,ethanol. Alternatively, the aminoheterocycle (1) can be treated with aninorganic or ammonium isothiocyanate, e.g., Meckler's procedure, in thepresence of an acid to afford the thiourea (2) in one step. Treatment ofthe thiourea (2) with an α-haloketone R¹³COCH₂X, wherein X=OTs, Cl, Br,I, or NR₃ (wherein R=C₁-C₆ alkyl), in a suitable base such astriethylamine, Hunig's base, DBU, alkali carbonate, sodium hydroxide,etc. and a suitable solvent such as ethanol affords the thiazole (3A).If the desired α-halo ketone R¹³COCH₂X is not commercially available, itcan be prepared by various methods known to those skilled in the art.Examples include, but are not limited to, bromination of commercially orreadily synthesized methyl ketones (Tetrahedron (1970) 5611-5615;Organic Synthesis (1946) 13-15; Tetrahedron (1990) 2943-2964),diazomethane treatment of carbonyl chlorides, oxidation of1-chloro-2-alkanols, bromination of silyl enol ethers, or halogenationof β-keto esters followed by decarboxylation. After formation of thethiazole (3A), protecting groups, if present, can be removed.

Scheme B shows an alternative method of preparing a compound of FormulaI. According to Scheme B, hydroxylated heteroaryl halide (5) (if notcommercially available) can be prepared from heteroaryl halide (4)by: 1) ortho metalation with LDA or another suitable base; 2) conversionof the anion to the boronate via reaction with B(OR)₃; and 3) oxidationof the boronate with a suitable oxidant such as N-methylmorpholine oxideor hydrogen peroxide. The ortho metalated species can also be quenchedwith (TMSO)₂ to obtain the hydroxylated material (5) directly uponacidic workup. The hydroxylated heteroaromatic compound (5) can bealkylated with R²X in the presence of a base such as, but not limitedto, cesium carbonate or sodium hydride and in a suitable solvent suchas, but not limited to, DMF to afford compound (6). Compound (6) can beconverted to compound (7) by the method of Hartwig et al. (for anexample of this transformation via analogy see: Organic Letters (2001)2729-2732), or by treatment with a Pd catalyst and benzophenone imine,or by heating in the presence of ammonia (or NH₂PG where PG is aprotecting group).

Compound (7) can be converted to compound (3) of Formula I upon reactionwith a halo-substituted thiazole or halo-substituted thiadiazole in thepresence of a base catalyst or metal (e.g., copper or palladium)catalyst. Alternatively, compound (6) can be converted directly to acompound (3) of Formula I upon treatment with an amino-substitutedthiazole or amino-substituted thiadiazole via base catalysis or viacopper or palladium catalysis; i.e., the Buchwald reaction. Afterformation of compound (3), protecting groups, if present, can beremoved.

Scheme C shows a method of preparing 2-aminothiazole and 2-halothiazoleintermediates (8) and (9), respectively, which are suitable for use inpreparing compounds of Formula I as shown in Scheme B. According toScheme C, α-haloketone R¹³COCH₂X can be treated with thiourea in thepresence of a suitable base such as potassium carbonate or triethylaminein an appropriate solvent such as DMF or ethanol to afford aminothiazole(8). The aminothiazole (8) can be converted to a diazonium saltintermediate by numerous methods including, but not limited to,treatment with sodium nitrite in acid or isobutylnitrite. Treatment ofthe in situ diazonium salt with Cu(X¹)₂ (X¹=Cl or Br) or HBr affords thecorresponding 2-halothiazole (9). Alternatively, using the Hantzschsynthetic method, the α-haloketone R¹³COCH₂X can be treated first withKSCN, then with HX wherein X is Cl or Br, to provide the 2-halothiazole(9). The 2-halothiazole compounds (8) and (9) can be converted intocompound (3A) by the methods shown in Scheme B.

Scheme D shows a method of preparing 5-amino-1,2,4-thiadiazole and5-chloro-1,2,4-thiadiazole intermediates (15) and (16), respectively,which are suitable for use in preparing compounds of Formula I as shownin Scheme B. According to Scheme D, primary amide (14) can be convertedinto 5-amino-1,2,4 thiadiazole (15) by heating with KSCN in anappropriate solvent such as methanol or ethanol (Adv. Heterocycl. Chem.,(1982) 32, 285). Formation of the diazonium salt of compound (15),followed by treatment of the in situ diazonium salt with CuCl₂ affordsthe corresponding 5-chloro-1,2,4-thiadiazole (16). The correspondingbromo derivative can also be synthesized through the use of CuBr₂.Alternatively, reaction of amidine (17) with perchloromethyl mercaptanaffords 5-chloro-1,2,4-thiadiazole (16) (Bioorg. Med. Chem., (2003) 11,5529-5537). Intermediates (15) and (16) can be converted into compound(3C) of Formula I by the methods shown in Scheme B.

Scheme E shows an alternative method of preparing compound (3G) ofFormula I. According to Scheme E, the halo-substituted heterocycle (28)(prepared by the method of Scheme A or B) wherein X¹ is Cl, Br or I, isfirst treated with an appropriate amount of methyl lithium solution toremove exchangeable proton(s), and then transmetalated with an alkyllithium reagent such as n-BuLi, sec-butyl or tert-butyl lithium, or aGrignard reagent such as, i-PrMg-halide. The resulting anion is thenquenched with an electrophile to provide compound (3G). After formationof compound (3G), protecting groups, if present, can be removed.

Scheme F shows a method of preparing compounds (3H) of Formula I from ahalo substituted heterocycle (28). According to Scheme F, thehalo-substituted heterocycle (28), prepared by the method of Scheme A orB, can be converted to a thiol (29) via one of several procedures.According to one method, the halo-substituted heterocycle (28) is firsttreated with an appropriate amount of methyl lithium solution to removeexchangeable proton(s), and then transmetalated with an alkyl lithiumreagent such as n-BuLi, sec-butyl or tert-butyl lithium, or a Grignardreagent such as, i-PrMg-halide. The resulting anion is quenched witheither elemental sulfur or bis(trimethylsilyl) peroxide to form thecorresponding mercapto-substituted compound (29). Alternatively, thehalide (28) can be converted under Pd-mediated conditions to thiol (29)utilizing potassium triisopropylsilanethiolate (Tetrahedron Letters(1994) 3225-3226). The thiol can be reacted with a variety ofelectrophiles using standard reaction conditions to provide thecorresponding ether (3H) of Formula I. Suitable electrophiles include,but are not limited to, activated heteroaryl halides such as, but notlimited to, 2-fluorocyanobenzene, 4-fluorocyanobenzene,2-fluoronitrobenzene, 4-fluoronitrobenzene, 2-chloro-4-nitropyridine,2-halopyridine, 2-halopyrimidine, 4-halopyrimidine, aryl halides andheteroaryl halides. After formation of compound (3H), protecting groups,if present, can be removed.

Scheme G shows an alternate method of adding the linker OR² to a coreheterocycle to provide a compound (3) of Formula I. According to SchemeG, a benzyl ether (32), prepared by the method of Scheme A or B, can beconverted to the hydroxyl substituted heterocycle (33), for example byhydrolysis with a strong acid (e.g., 6N HCl) or by hydrogenation (e.g.,H₂ or ammonium formate in the presence of a metal catalyst). Alkylationof the hydroxylated heterocycle (33) with R²X, wherein X=F, Cl, Br, I,or NR₃ (where R is C₁-C₆ alkyl) in the presence of a base such as, butnot limited to, cesium carbonate, in a suitable solvent such as, but notlimited to, DMF, or via copper or palladium catalysis (i.e., the Ullmanreaction) affords compound (3) of Formula I. After formation of compound(3), protecting groups, if present, can be removed.

Scheme H shows an alternative method of preparing a compound (3 L) ofFormula I. According to Scheme H, the 2-aminopyridine (38) isregioselectively brominated with a suitable brominating agent such asNBS or bromine to provide compound (39). The brominated compound can beconverted to compound (40) upon reaction with R²LH (wherein L is O) inthe presence of a suitable base such as cesium carbonate, sodium hydrideor triethylamine in the presence of a metal catalyst (i.e.; CuI orPd₂dba₃) in a suitable solvent such as DMSO or DMF. The chlorinatedproduct (40) can be converted to compound (41) by the method of SchemeA, B or L. Compound (41) can be converted to a 5-substituted compound (3L) of Formula I by the method of Scheme E or F. Alternatively, thechlorinated 2-aminopyridine (40) can be converted to a 5-substitutedcompound (42) by the method of Scheme E or F, and then the thiazolyl orthiadiazolyl group can be added to compound (42) by the method of SchemeA, B or L to provide compound (3 L). After formation of compound (3 L),protecting groups, if present, can be removed.

Scheme I shows an alternative method of preparing a compound (3 L) ofFormula I. According to Scheme I, reaction of compound (43) with R²LH(where L is O) in the presence of a suitable base such cesium carbonateor sodium hydride either with or without a metal catalyst (i.e.; Pd₂dba₃or CuI) in DMSO or DMF affords compound (44) wherein L is O.

The 2-aminopyridine (44) is then regioselectively brominated with asuitable brominating agent such as NBS or bromine to provide compound(45). The brominated product (45) can be converted to compound (46) bythe method of Scheme A, B or L. Compound (46) can be converted to5-substituted compounds (3 L) of Formula I by the method of Scheme E orF. Alternatively, the brominated 2-aminopyridine (45) can be convertedto a 5-substituted compound (47) by the method of Scheme E or F, andthen the thiazolyl or thiadiazolyl group can be added to compound (47)by the method of Scheme A, B or L to provide compound (3 L). Afterformation of compound (3 L), protecting groups, if present, can beremoved.

Scheme J shows an alternative method of preparing a compound (3L) ofFormula I. According to Scheme J, reaction of compound (48) (which ifnot commercially available can be made from commercial aminopyridinesvia regioselective bromination) in the presence of a suitable base suchcesium carbonate or sodium hydride and with or without a metal catalyst(e.g., Pd₂ dba₃ or CuI) in DMSO or DMF affords compound (49) by a methodsuch as: ipso replacement using R⁶SH; Buchwald thioether formation withR⁶SH, etc., according to procedures well known in the literature. The2-aminopyridine (49) is then regioselectively brominated with a suitablebrominating agent such as NBS or bromine to provide compound (50). Thebrominated product (50) can be converted to compound (51) by the methodof Scheme A, B or L. Compound (51) can be converted to 5-substitutedcompounds (3L) of Formula I by Buchwald ether formation with R²OH.Alternatively, the brominated 2-aminopyridine (50) can first beconverted to compound (52) by the Buchwald chemistry, and compound (52)can be converted to compound (3L) by the method of Scheme A, B or L.After formation of compound (3L), protecting groups, if present, can beremoved.

Scheme K shows an alternative method of preparing a compound (3L) ofFormula I. Treatment of compound (53) with R²X in the presence of asuitable base such as cesium carbonate or sodium hydride, with orwithout a metal catalyst, affords compound 54. Subsequently, compound(54) can be regioselectively brominated to afford compound (55). Thiscompound can be converted to compound (56) via the methods described inSchemes E or F. Compound (56) is then converted to compound (3L) via theprocedures found in Schemes A, B or L. Alternatively, compound (55) canbe converted to compound (57) via the procedures found in Schemes A, Bor L, and then converted to compound (3L) via the procedures found inSchemes E or F. After formation of compound (3L), protecting groups, ifpresent, can be removed.

Scheme L shows an alternative method for producing compounds of theformula 3C wherein D² is N. Formation of oxime (80) from aldehyde (79)allows for the chlorination with N-chlorosuccinimide in a suitablesolvent, such as DMF, to produce compound (81). Compound (81) issulfonylated with a sulfonyl chloride having the formula R′SO₂Cl whereinR′ is, C₁-C₆ alkyl (for example, methyl) or aryl optionally substitutedwith C₁-C₆ alkyl (for example, tolyl) in the presence of a base, such asbut not limited to triethylamine, to afford compound (82) with athiocyanate salt, such as NaNCS, in a suitable solvent, such asacetonitrile, and in the presence of a base, such as but not limited topyridine, affords the activated intermediate (83) (see, for example,Takeuchi, K., JP 2001081084). Intermediate (83) can be reacted in situwith an appropriate amino heterocycle (7) to afford compound (3C) ofFormula I. After formation of compound (3C), protecting groups, ifpresent, can be removed.

Scheme M shows an alternative method for the construction of compoundsof Formula I. Starting from the commercially available 2-cyanopyridine(84), selective nucleophilic displacement can be achieved with compoundsof the formula R²LH and an appropriate base, such as sodium hydride, ina suitable solvent, such as DMF to provide compound (85). Addition of asecond nucleophile having the formula R⁶SH, under similar conditions,affords the functionalized 2-cyanopyridine (86). Hydrolysis of thenitrile can occur under many conditions, with NaOH in aqueous ethanolbeing preferred, to afford the picolinate (87). Curtius rearrangement inthe presence of an appropriate alcohol affords the carbamate (88). Thecarbamate can be removed using various conditions, depending on thealcohol used in the previous step, to provide the 2-aminopyridine (89).Using procedures outlined in Schemes A, B or L, compound (90) of theFormula I can be synthesized from compound (89). After formation ofcompound (90), protecting groups, if present, can be removed.

Scheme N shows another alternative method for the construction ofcompounds of Formula I. Starting from the commercially available5-bromo-3-nitropicolinonitrile (84), selective nucleophilic displacementcan be achieved with compounds of the formula R²LH and an appropriatebase, such as sodium hydride, in a suitable solvent, such as DMF toprovide compound (85). Addition of a second nucleophile having theformula R⁶SH, under similar conditions, affords the functionalized2-cyanopyridine (86). Hydrolysis of the nitrile to the amide (91) canoccur under standard conditions, such as with concentrated H₂SO₄. AHofmann reaction to convert (91) to the aminopyridine (92) can occurunder standard conditions, such as with NaOBr. Using procedures outlinedin Schemes A, B or L, compound (93) of the Formula I can be synthesizedfrom compound (92). After formation of compound (93), protecting groups,if present, can be removed.

Scheme O shows an alternative method for the construction of compoundsof Formula I. Starting from the commercially available substitutedpyridine (94) in which X is Br or Cl, selective nucleophilicdisplacement can be achieved with compounds of the formula R²LH and anappropriate base, such as sodium hydride, in a suitable solvent, such asDMF to provide compound (95). Hydrolysis of the nitrile to the amide(96) can occur under standard conditions, such as with concentratedH₂SO₄. A Hofmann reaction to convert (96) to the aminopyridine (97) canoccur under standard conditions, such as with NaOBr. Using proceduresoutlined in Schemes A, B, E, F or L, compound (98) of the Formula I canbe synthesized from compound (97). After formation of compound (98),protecting groups, if present, can be removed.

Scheme P shows a method of synthesizing compounds of Formula I where R³is CF₃ (105). The 2,3-dichloro-5-(trifluoromethyl)pyridine (99) isreacted with DMAP, followed by a cyanide source, such as NaCN, toprovide the cyanopyridine (100). Nucleophilic displacement of thechlorine with compounds of the formula R²LH and an appropriate base,such as sodium hydride, in a suitable solvent, such as DMF providescompound (101). Utilizing the routes in Schemes M or N the cyanopyridine(101) can be converted into the aminopyridine (103). Using proceduresoutlined in Schemes A, B, or L, compounds (105) of the Formula I can besynthesized from compound (103). After formation of compound (105),protecting groups, if present, can be removed.

Scheme Q shows a method of synthesizing compounds of Formula I wheren=0-2 and each R^(x) is independently selected from hydrogen or a(1-2C)alkyl group. The pendant alkene in compound (106), which can besynthesized from the methods in schemes A, B or L, can be dihydroxylatedby a variety of conditions, such as but not limited to, treatingcompound (106) with an oxidizing agent such as OsO₄ to provide the diol(107). Alternatively, compound (107) can be prepared in a chiral mannerthrough the use of reagents or kits such as, but not limited to,AD-mix-α (K₂OsO₂(OH)₄, (DHQ)₂-PHAL (a chiral quinine ligand) and eitherpotassium ferricyanide or N-methylmorpholine N-oxide) and AD-mix-β(K₂OsO₂(OH)₄, (DHQD)₂-PHAL (a chiral quinine ligand) and eitherpotassium ferricyanide or N-methylmorpholine N-oxide). Additionally, thealkene (106) can be oxidized to the epoxide (108), which can behydrolyzed to provide the diol (107).

Scheme R shows an alternative method of synthesizing compounds ofFormula I where n=0-2 and each R^(x) is independently selected fromhydrogen or a (1-2C)alkyl group. According to the Scheme R, epoxide(108) can be opened with a cyanide source, such as NaCN, to affordcompound (109). Compound (109) can be reacted with one or twoequivalents of an alkali metal hydride reagent (for example LiAlH₄,DIBAL-H or BH₃) or an organometallic reagent R^(x)M or (R^(x))₂M where Mis a metal (for example R^(x)Li, (R^(x))₂Zn or (R^(x))₂CuLi) to affordcompound (110) or (111), respectively. Alternatively, compound (110) canbe further reduced with an alkali metal hydride reagent (for exampleLiAlH₄, DIBAL-H or BH₃) or an organometallic reagent R^(x)M or (R^(x))₂Mwhere M is a metal (for example, R^(x)Li, (R^(x))₂Zn or (R^(x))₂CuLi) toafford compound (111).

Scheme S shows the synthesis of compounds of Formula I where n=0-2 andeach R^(x) is independently selected from H or a (1-2C)alkyl group.Carbonyl compound (112), which can be synthesized by methods in SchemesA, B or L, can be converted to the cyanohydrin (113). The cyanohydrin(113) can be treated with 1 or 2 equivalents of an alkali metal hydridereagent (for example LiAlH₄, DIBAL-H or BH₃) or an organometallicreagent R^(x)M or (R^(x))₂M where M is a metal (for example, R^(x)Li,(R^(x))₂Zn or (R^(x))₂CuLi) to provide compound (114) or (115),respectively. Alternatively, compound (114) can be further reacted withan alkali metal hydride reagent R^(x)M or (R^(x))₂M where M is a metal(for example LiAlH₄, DIBAL-H or BH₃) or an organometallic reagent (forexample, R^(x)Li, (R^(x))₂Zn or (R^(x))₂CuLi) to afford compound (115).

Accordingly, another embodiment of the invention provides a method forpreparing a compound of Formula I or a salt thereof, comprising:

(a) reacting a corresponding compound of the formula (II)

with a compound of the formula (III)

in the presence of a base catalyst or metal catalyst; or

(b) reacting a corresponding compound of the formula (IV)

with a compound of the formula (V)

wherein X is a leaving atom or group in the presence of a base catalystor metal catalyst; or

(c) for a compound of Formula I wherein D² is CH, reacting acorresponding compound of the formula (VI)

with a compound of the formula R¹³COCH₂X, wherein X is a leaving groupor atom in the presence of a base; or

(d) for a compound of Formula I wherein D² is N, reacting acorresponding compound of the formula (VII)

with a compound having the formula (VIII)

where R′ is C1-C6 alkyl or aryl optionally substituted with C1-C6 alkyl,in the presence of a base; or

(e) for compounds of Formula I where R³ is SR⁶, reacting a correspondingcompound having the formula (IX)

with a compound having the formula R⁶SH in the presence of a suitablebase; or

(f) reacting a corresponding compound having the formula (XI)

wherein X^(a) is a leaving atom or group, with a compound having theformula R³—X^(b) where X^(b) is a leaving atom or a leaving group, inthe presence of a suitable base; or

(g) for compounds of Formula I where R³ is SR⁶, reacting a correspondingcompound having the formula (XII)

with a compound having the formula R⁶—X^(c) wherein X^(c) is a leavingatom or group in the presence of a suitable base; or

(h) for compounds of Formula I where L is O, reacting a correspondingcompound having the formula (XIII)

with a compound having the formula R²—X^(d), wherein X^(d) is a leavingatom or group in the presence of a base or in the presence of a copperor palladium catalyst; or

(i) reacting a corresponding compound having the formula (XIV)

wherein X^(c) is a leaving group or atom, with a compound having theformula R²LH wherein L is O or S, in the presence of a palladiumcatalyst and a suitable base; or

(j) for a compound of Formula I where R¹³ has the formula

wherein each R^(x) is independently selected from hydrogen and a (1-2Calkyl) group and n is 0-2, reacting a corresponding compound having theformula (XV)

with an oxidizing agent; or

(k) for a compound of Formula I where R¹³ has the formula

hydrolyzing a corresponding compound having the formula (XVI)

wherein each R^(x) is independently selected from hydrogen and a (1-2Calkyl) group and n is 0-2; or

(l) for a compound of Formula I wherein R¹³ has the formula

wherein each R^(x) is independently selected from hydrogen and a (1-2Calkyl) group and n is 0-2, reacting a corresponding compound having theformula (XVII)

with two equivalents of a metal hydride reagent or an organometallicreagent having the formula R^(x)M or (R^(x))₂M where each R^(x) isindependently selected from hydrogen and a (1-2C alkyl) group and M is ametal anion; or

(m) for a compound of Formula I wherein R¹³ has the formula

wherein each R^(x) is independently selected from hydrogen and a (1-2Calkyl) group and n is 0-2, reacting a corresponding compound having theformula (XVIII)

with a metal hydride reagent or an organometallic reagent having theformula R^(x)M or (R^(x))₂M where each R^(x) is independently selectedfrom hydrogen and a (1-2C alkyl) group and M is a metal anion; or

(n) for a compound of Formula I wherein R¹³ has the formula

wherein each R^(x) is independently selected from hydrogen and a (1-2Calkyl) group and n is 0-2, reacting a corresponding compound having theformula (XIX)

with two equivalents of a metal hydride reagent or an organometallicreagent having the formula R^(x)M or (R^(x))₂M where each R^(x) isindependently selected from hydrogen and a (1-2C alkyl) group and M is ametal anion; or

(o) for a compound of Formula I wherein R¹³ has the formula

wherein each R^(x) is independently selected from hydrogen and a (1-2Calkyl) group and n is 0-2, reacting a corresponding compound having theformula (XX)

with a metal hydride reagent or an organometallic reagent having theformula R^(x)M or (R^(x))₂M where each R^(x) is independently selectedfrom hydrogen and a (1-2C alkyl) group and M is a metal anion; and

removing any protecting group or groups and, if desired, forming a salt.

Referring to method (b), X can be a leaving atom (for example, Cl, Br)or a leaving group (e.g., OTs or OTf).

Referring to method (c), X can be a leaving group (such as OTs or NR₃wherein R is C₁C₆ alkyl) or a leaving atom (for example Cl, Br, or I).

Referring to method (e), a suitable base may be, for example, an alkyllithium base such as methyl lithium, butyl lithium, or a mixturethereof.

Referring to method (f), X^(a) can be a leaving atom such as a halogen(e.g., F, Cl or Br) or a leaving group such as a sulfonate (e.g., OMs orOTs). X^(b) may be a leaving atom such as a halogen (e.g., F, Cl or Br)or a leaving group such as a sulfonate (e.g., OMs or OTs). A suitablebase may be, for example, an alkali metal alkoxide such as potassiumt-butoxide.

Referring to method (g), X^(c) may be a leaving atom such as a halogen,such as Br, Cl or I. A suitable base may be, for example, an alkyllithium such as methyl lithium, butyl lithium, or a combination thereof.

Referring to method (h), X^(d) may be a leaving atom such as a halogen(e.g., F, Cl or Br) or a leaving group such as a sulfonate (e.g., OMs orOTs).

Referring to method (i), X^(e) may be a leaving group or atom e.g., ahalogen such as Cl or Br; or a triflate or tosylate group. Suitablebases include alkali metal carbonates such as CsCO₃.

Referring to method (j), suitable oxidizing agents include OsO₄, KMnO₄,AD-mix-α, AD-mix-β and the like.

Referring to method (k), the hydrolysis of the epoxide can take placeunder either acidic or basic conditions.

Referring to methods (l), (m), (n) and (o), suitable metal hydridereagents include LiAlH₄, DIBAL-H and BH₃.

Referring to methods (l), (m), (n) and (o), suitable organometallicreagents include alkyl lithium, alkyl zinc, and alkyl cuprate reagents.

The compounds of Formulas (IX, (XI), (XII), (XIII), (XIV), (XV), (XVI),(XVII), (XVIII), (XIX), and (XX) are also believed to be novel and areprovided as further aspects of this invention.

In preparing compounds of Formula I, protection of remotefunctionalities (e.g., primary or secondary amines, etc.) ofintermediates may be necessary. The need for such protection will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. Suitable amino-protecting groups (NH-Pg)include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Theneed for such protection is readily determined by one skilled in theart. For a general description of protecting groups and their use, seeT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

The compounds of the present invention can be used as prophylactics ortherapeutic agents for treating diseases or disorders mediated bydeficient levels of glucokinase activity or which can be treated byactivating glucokinase including, but not limited to, diabetes mellitus,impaired glucose tolerance, IFG (impaired fasting glucose) and IFG(impaired fasting glycemia), as well as other diseases and disorderssuch as those discussed below. Furthermore, the compounds of the presentinvention can be also used to prevent the progression of the borderlinetype, impaired glucose tolerance, IFG (impaired fasting glucose) or IFG(impaired fasting glycemia) to diabetes mellitus.

Accordingly, another aspect of the invention provides methods oftreating or preventing diseases or conditions described herein byadministering to a mammal, such as a human, a therapeutically effectiveamount of a compound of Formula I.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein.

The amount of a compound of Formula I that will correspond to such anamount will vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of themammal in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art.

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired physiological change ordisorder. For purposes of this invention, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.Those in need of treatment include those already with the condition ordisorder as well as those prone to have the condition or disorder orthose in which the condition or disorder is to be prevented.

As used herein, the term “mammal” refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

In certain embodiments, the methods of this invention are useful fortreating diabetes mellitus. Diabetes mellitus is a condition where thefasting plasma glucose level (glucose concentration in venous plasma) isgreater than or equal to 126 mg/dL (tested on two occasions) and the2-hour plasma glucose level of a 75 g oral glucose tolerance test (OGTT)is greater than or equal to 200 mg/dL. Additional classic symptomsinclude polydipsia, polyphagia and polyuria.

In certain embodiments, the methods of this invention are useful fortreating the syndrome of impaired tolerance (IGT). IGT is diagnosed bythe presentation of a fasting plasma glucose level of less than 126mg/dL and a 2-hour post-oral glucose challenge lever greater than 140mg/dL.

The compounds of the present invention can be also used as prophylacticsor therapeutic agents of diabetic complications such as, but not limitedto, neuropathy, nephropathy, retinopathy, cataract, macroangiopathy,osteopenia, diabetic hyperosmolar coma), infection, dermal soft tissueinfection, lower limb infection etc.), diabetic gangrene, xerostomia,decreased sense of hearing, cerebrovascular disease, peripheralcirculatory disturbance, etc.

The compounds of the present invention can be also used as prophylacticsor therapeutic agents in the treatment of diseases and disorders suchas, but not limited to, obesity, metabolic syndrome (syndrome X),hyperinsulinemia, hyperinsulinemia-induced sensory disorder,dyslipoproteinemia (abnormal lipoproteins in the blood) includingdiabetic dyslipidemia, hyperlipidemia, hyperlipoproteinemia (excess oflipoproteins in the blood) including type I, II-a(hypercholesterolemia), II-b, III, IV (hypertriglyceridemia) and V(hypertriglyceridemia), low HDL levels, high LDL levels, atherosclerosisand its sequelae, vascular restenosis, neurodegenerative disease,depression, CNS disorders, liver steatosis, osteoporosis, hypertension,renal diseases (e.g., diabetic nephropathy, glomerular nephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,terminal renal disorder etc.), myocardiac infarction, angina pectoris,and cerebrovascular disease (e.g., cerebral infarction, cerebralapoplexy).

The compounds of the present invention can be also used as prophylacticsor therapeutic agents in the treatment of diseases and disorders suchas, but not limited to, osteoporosis, fatty liver, hypertension, insulinresistant syndrome, inflammatory diseases (e.g., chronic rheumatoidarthritis, spondylitis deformans, osteoarthritis, lumbago, gout,postoperative or traumatic inflammation, remission of swelling,neuralgia, pharyngolaryngitis, cystitis, hepatitis (includingnon-alcoholic steatohepatitis), pneumonia, inflammatory colitis,ulcerative colitis), pancreatitis, visceral obesity syndrome, cachexia(e.g., carcinomatous cachexia, tuberculous cachexia, diabetic cachexia,hemopathic cachexia, endocrinopathic cachexia, infectious cachexia,cachexia induced by acquired immunodeficiency syndrome), polycysticovary syndrome, muscular dystrophy, tumor (e.g., leukemia, breastcancer, prostate cancer, skin cancer etc.), irritable bowel syndrome,acute or chronic diarrhea, spondylitis deformans, osteoarthritis,remission of swelling, neuralgia, pharyngolaryngitis, cystitis, SIDS,and the like.

The compounds of the present invention can be used in combination withone or more additional drugs, for example a compound that works by thesame or a different mechanism or action, such as insulin preparations,agents for improving insulin resistance, alpha-glucosidase inhibitors,biguanides, insulin secretagogues, dipeptidylpeptidase IV (DPP IV)inhibitors, beta-3 agonists, amylin agonists, phosphotyrosinephosphatase inhibitors, gluconeogenesis inhibitors, sodium-glucosecotransporter inhibitors, known therapeutic agents for diabeticcomplications, antihyperlipidemic agents, hypotensive agents, andantiobesity agents. An example of an agent for improving insulinresistance is an agonist for peroxisome proliferator-activatedreceptor-gamma (PPAR gamma).

The compounds of the invention may be administered by any convenientroute, e.g. into the gastrointestinal tract (e.g. rectally or orally),the nose, lungs, musculature or vasculature or transdermally. Thecompounds may be administered in any convenient administrative form,e.g. tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulkingagents, and further active agents. If parenteral administration isdesired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion. Such compositionsform a further aspect of the invention.

According to another aspect, the present invention provides apharmaceutical composition, which comprises a compound of Formula I or apharmaceutically acceptable salt thereof, as defined hereinabove. In oneembodiment, the pharmaceutical composition includes the compound ofFormula I together with a pharmaceutically acceptable diluent orcarrier.

This invention also provides the use of a compound of Formula I in thetreatment of diseases or disorders mediated by deficient levels ofglucokinase activity or which can be treated by activating glucokinase.

An additional aspect of the invention is the use of a compound ofFormula I in the preparation of a medicament for the treatment orprevention of diseases or disorders mediated by deficient levels ofglucokinase activity or which can be treated by activating glucokinase.

EXAMPLES

The following examples illustrate the invention. In the examplesdescribed below, unless otherwise indicated all temperatures are setforth in degrees Celsius. Reagents were purchased from commercialsuppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge,and were used without further purification unless otherwise indicated.Tetrahydrofuran (THF), dichloromethane (CH₂Cl₂, methylene chloride),toluene, and dioxane were purchased from Aldrich in Sure seal bottlesand used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

¹HNMR spectra were obtained as CDCl₃, CD₃OD, D₂O or d6-DMSO solutions(reported in ppm), using tetramethylsilane (0.00 ppm) or residualsolvent (CDCl₃: 7.25 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79 ppm; d6-DMSO: 2.50ppm) as the reference standard. When peak multiplicities are reported,the following abbreviations are used: s (singlet), d (doublet), t(triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt(doublet of triplets). Coupling constants, when given, are reported inHertz (Hz).

Example 1(S)-1-(5-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol

Step A: To a solution of (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde(9.0 g, 52.9 mmol) in THF (120 mL and 60 mL of water) was added hydroxylamine hydrochloride (3.73 g, 52.9 mmol) and the reaction stirred untilclear (10 minutes). Sodium carbonate (2.75 g, 25.9 mmol) was added andthe reaction stirred overnight at ambient temperature. The reaction waspoured into ethyl acetate (500 mL) and the layers were separated. Theorganics were washed with water (200 mL), brine (200 mL), dried overmagnesium sulfate and concentrated in vacuo to yield(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (9.08 g, 49 mmol,92.7%).

Step B: To a solution of (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehydeoxime (9.08 g, 49 mmol) in DMF (50 mL) was added1-chloropyrrolidine-2,5-dione (7.20 g, 53.9 mmol) and the reactionstirred overnight at ambient temperature. The reaction was poured intowater (500 mL) extracted with ether. The organics were washed with brineand dried over magnesium sulfate. The material was concentrated in vacuoto yield (R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride(10.4 g, 47 mmol, 96.6%).

Step C: To a solution of(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (10.4 g,47.3 mmol) cooled to 0° C. in THF (150 mL) was added methanesulfonylchloride (5.97 g, 52.1 mmol) followed byN-ethyl-N-isopropylpropan-2-amine (6.75 g, 52.1 mmol) and the reactionstirred for 1 hr at ambient temperature. The reaction was concentratedin vacuo. The material was dissolved in dichloromethane andchromatographed using 8:1 Hexane/EtOAc to 4:1 Hexane/EtOAc (2 columns)to give the(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride as a viscous oil that solidified on standing (12 g, 40 mmol,85% yield).

Step D: A flask was charged with 2-methylpyridin-3-ol (3.0 g, 27.5 mmol)and DMF (100 mL). Sodium hydride (0.760 g, 30.2 mmol) was added andstirred for 5 minutes. 5-Bromo-3-nitropicolinonitrile (6.26 g, 27.5mmol) was added and stirred for 10 minutes. The reaction was poured intoa flask containing 300 mL saturated NH₄Cl and 300 mL water with vigorousstirring. The solids were filtered and dried under high vacuum to afford5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (7.78 g, 97.6% yield)as light tan solid.

Step E: A flask was charged with5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (60 g, 207 mmol) andsulfuric acid (203 g, 2068 mmol). The reaction was stirred at ambienttemperature overnight. Water (500 mL) was added carefully andneutralized using 50% sodium hydroxide to pH 5.0. The mixture wasextracted with dichloromethane and ethyl acetate, dried and concentratedto afford 5-bromo-3-(2-methylpyridin-3-yloxy)picolinamide (63.0 g, 204mmol, 98.9% yield) as yellow solid.

Step F: A flask was charged with 2M sodium hydroxide (256 ml, 511 mmol)and cooled to 0° C. Bromine (7.85 ml, 153 mmol) was added and stirredfor 15 minutes. 5-bromo-3-(2-methylpyridin-3-yloxy)picolinamide (31.5 g,102 mmol) in dioxane (650 mL) was added and stirred at ambienttemperature overnight. The aqueous layer was extracted with ethylacetate and CH₂Cl₂. The organic layers were washed with water, brine,dried, concentrated and purified over silica gel (25-50-75-100% ethylacetate in hexanes) to afford5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (12 g, 43 mmol, 41.9%yield) as a yellow solid.

Step G:(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (1.86 g, 6.25 mmol), pyridine (1.13 g, 14.3 mmol) and sodiumthiocyanate (0.58 g, 7.14 mmol) were dissolved in acetonitrile (45 mL).The solution was heated to 40° C. for 40 minutes.5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (1.0 g, 3.57 mmol)was added and the reaction was heated at 60° C. overnight. The solutionwas cooled to 0° C., filtered and the solid was dried to give(S)-N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.90 g, 1.78 mmol, 50% yield) as a white solid.

Step H: To a solution of(S)-N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.072 g, 0.20 mmol) in methanol (10 mL) was added concentrated HCl (3drops) and the reaction heated to 80° C. for 3 hr. The reaction wasconcentrated in vacuo. The material was triturated with ethylacetate/methanol 1/1 (10 mL) to give(S)-1-(5-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridine-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol(0.070 g, 0.16 mmol, 83%) as a white solid (APCI POS 424,426 M+H).

Example 2(S)-1-(5-(5-trifluoromethyl-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol

(S)-1-(5-(5-trifluoromethyl-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol(APCI POS 414 M′H) was synthesized following the procedure in example 1substituting 5-trifluoromethyl-3-chloropicolinonitrile for5-bromo-3-nitropicolinonitrile in step D.

Example 3(S)-1-(5-(5-phenylthio-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol

Step A: To a solution of 2-methylpyridin-3-ol (0.96 g, 8.8 mmol) in DMF(10 mL) cooled to 0° C. was added NaH (0.35 g, 8.8 mmol) in portions andthe reaction warmed to ambient temperature. To this mixture was added5-bromo-3-nitropicolinonitrile (2.0 g, 8.8 mmol) and the reactionstirred over night at ambient temperature. To the reaction was addedthiophenol (0.96 g, 8.8 mmol) and the reaction cooled to 0° C. NaH (0.35g, 8.8 mmol) was added and the reaction warmed to ambient temperatureand the reaction stirred at ambient temperature overnight. The reactionwas poured into water (1000 mL) and the aqueous layer was extracted withether (3×100 mL). The organics were washed with 1N NaOH (100 mL), water(2×100 mL) brine (100 mL), dried over MgSO₄ and concentrated in vacuo togive 5-phenylthio-3-(2-methylpyridin-3-yloxy)picolinonitrile (2.8 g, 8.8mmol, 100%) as a solid.

Step B:(S)-1-(5-(5-phenylthio-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol (APCI POS 454 M+H) was synthesized following theprocedure in Example 1 substituting5-phenylthio-3-(2-methylpyridin-3-yloxy)picolinonitrile for5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile in step E.

Example 4(S)-1-(5-(5-phenylthio-3-(pyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethane-1,2-diol

(S)-1-(5-(5-phenylthio-3-(pyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethane-1,2-diol(APCI POS 440 M+H) was synthesized following the procedure in example 3substituting pyridin-3-ol for 2-methylpyridin-3-ol in step A.

Example 5(S)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol

(S)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol(APCI POS 455 M+H) was synthesized following the procedure in example 3substituting 2-thiopyridine for thiophenol in step A.

Example 6(S)-1-(5-(5-(2-hydroxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol

Step A: To dioxanes (50 mL) bubbled continuously with N₂ was added inthis order Pd₂dba₃ (0.041 g, 0.046 mmol), Xanphos (0.055 g, 0.091 mmol),(S)-N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.46 g, 0.091 mmol), ethyl 2-mercaptoacetate (0.11 g, 0.091 mmol) andHunig's base (0.12 g, 0.091 mmol) and the reaction was heated to 80° C.for 6 hr. The reaction was concentrated in vacuo and the materialchromatographed using 40% EtOAc as eluent to give(S)-ethyl-2-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)1,2,4-thiadiazo-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)acetate(0.30 g, 0.55 mmol).

Step B: To a solution of(S)-ethyl-2-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)1,2,4-thiadiazo-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)acetate(0.30 g, 0.55 mmol) in THF (20 mL) cooled to 0° C. was added LiAlH₄ (1 Msolution in THF) (0.55 mL, 0.55 mmol) and the reaction stirred for 3hours while warming to ambient temperature. The reaction was quenched bythe addition of water and poured into ethyl acetate (100 mL) and thelayers were separated. The organics were washed with brine, dried overMgSO₄ and concentrated in vacuo to give (S)_(:)2-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)1,2,4-thiadiazo-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridine-3-ylthio)ethanol(0.28 g, 0.55 mmol).

Step C:(S)-1-(5-(5-(2-hydroxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridine-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol(APCI POS 422 M+H) was synthesized following the procedure in example 1substituting(S)-2-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)1,2,4-thiadiazo-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridine-3-ylthio)ethanolfor(S)-N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-aminein step H.

Example 7(S)-1-(5-(3-(4-fluorophenoxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol

Step A: A flask was charged with 4-fluorophenol (44 g, 365 mmol) and DMF(500 mL). The reaction was cooled to 0° C. Sodium hydride (16.6 g, 414mmol) was added and stirred for 10 minutes.5-Bromo-3-nitropicolinonitrile (90 g, 395 mmol) was added and themixture stirred at ambient temperature for 30 minutes. The reaction waspoured into a flask containing water (5000 mL) and stirred for 10minutes. The pH was adjusted to 10 to give5-bromo-3-(4-fluorophenoxy)picolinonitrile (121 g, 413 mmol, 105% yield)as a solid.

Step B: To a solution of pyridine-2-thiol (2.5 g, 23 mmol) in DMA (25mL) cooled to 0° C. was added NaH (0.90 g, 23 mmol) and the reactionstirred at ambient temperature for 20 min, followed by addition of the5-bromo-3-(4-fluorophenoxy)picolinonitrile (6.6 g, 23 mmol) and stirringover night at ambient temperature. The reaction was poured into water(250 mL) and a solid formed. The solid was collected, washed with water,and dried in vacuo to yield3-(4-fluorophenoxy)-5-(pyridin-2-ylthio)picolinonitrile (5 g, 16 mmol,70%).

Step C:(S)-1-(5-(3-(4-fluorophenoxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol(APCI POS 458 M+H) was synthesized following the procedure in example 1substituting 3-(4-fluorophenoxy)-5-(pyridin-2-ylthio)picolinonitrile for5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile in step E.

Example 8(R)-1-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol

Step A: A flask was charged with5-bromo-3-(4-fluorophenoxy)picolinonitrile (10 g, 34 mmol) and sulfuricacid (50 mL). The reaction was stirred at ambient temperature overnight.Water (500 mL) was added carefully and the mixture was adjusted to pH5.0 using 50% sodium hydroxide. The mixture was extracted withdichloromethane and ethyl acetate, dried and concentrated to afford5-bromo-3-(4-fluorophenoxy)picolinamide (10.6 g, 34 mmol, 100% yield) asyellow solid.

Step B: A flask was charged with 2M sodium hydroxide (115 ml, 230 mmol)and cooled to 0° C. Bromine (9.3 g, 58 mmol) was added and the mixturestirred for 15 minutes. 5-bromo-3-(4-fluorophenoxy)picolinamide (15.8 g,51 mmol) in dioxane (200 mL) was added and the mixture stirred atambient temperature overnight. The aqueous layer was extracted withethyl acetate and CH₂Cl₂. The organic layers were washed with water,brine, dried over MgSO₄, concentrated and purified by chromatography(25-50-75-100% ethyl acetate in hexanes) to afford5-bromo-3-(2-fluorophenoxy)pyridin-2-amine (12 g, 42 mmol, 82% yield) asa yellow solid.

Step C: To a solution of the 5-bromo-3-(2-fluorophenoxy)pyridin-2-amine(17 g, 60 mmol, in THF (500 mL) was added benzoyl isothiocyante (9.8 g,60 mmol) and the reaction stirred at ambient temperature overnight. Thereaction was poured into hexanes (2 L), the solid was collected anddried in vacuo to giveN-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylcarbamothioly)benzamide (25 g,56 mmol, 93% yield).

Step D: To a solution ofN-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylcarbamothioly)benzamide (25 g,56 mmol) in ethanol (150 mL) was added NaOH (2 M) (56 mL, 112 mmol) andthe reaction stirred ON at 80° C. The mixture was poured into water andthe slurry filtered. The collected solid was dried in vacuo to yield1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (15.4 g, 45 mmol).

Step E: To a solution of (S)-methyl2,2-dimethyl-1,3-dioxolane-4-carboxylate (1.3 g, 8.1 mmol) andchloroiodomethane (4.3 g, 24 mmol) in THF (50 mL) at −78° C. was added asolution of LDA (16.2 mL, 24 mmol) in portions over 10 minutes. Thereaction was stirred at −78° C. After addition, the slurry was warmed toambient temperature. The reaction was poured into EtOAc (200 mL) and theaqueous layer basified using 1 N NaOH. The organics were separated andwashed with brine, dried over MgSO₄ and concentrated in vacuo. Thematerial was purified by chromatography using DCM as eluent to give(S)-2-chloro-1-(2,2-dimethyl-1,3-dioxolane-4-yl)ethanone (0.60 g, 3.4mmol, 42% yield) as an oil.

Step F: To 1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (0.5 g,1.5 mmol) in ethanol (50 mL) was added(S)-2-chloro-1-(2,2-dimethyl-1,3-dioxolane-4-yl)ethanone (0.34 g, 1.9mmol) and the reaction stirred at 80° C. for 1 hr. The reaction waspoured into water (250 mL) and the filtered. The solid was trituratedwith ethyl acetate and methanol. The solid was suspended in ethylacetate (500 mL) and washed with 1 N NaOH (500 mL). The organics wereconcentrated and the crude material was purified by chromatography using3 to 10% MeOH/CH₂Cl₂ as eluent to give(R)-1-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol(0.043 g, 0.10 mmol, 7%) (APCI POS 426, 428 M+H).

Example 9(S)-1-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol

(S)-1-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol(APCI POS 426, 428 M+H) was synthesized following the procedure inexample 8 substituting (R)-methyl2,2-dimethyl-1,3-dioxolane-4-carboxylate for (S)-methyl2,2-dimethyl-1,3-dioxolane-4-carboxylate in step E.

Example 10(R)-1-(2-(3-(4-fluorophenoxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol

(R)-1-(2-(3-(4-fluorophenoxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol(APCI POS 457 M+H) was synthesized following the procedure in example 8substituting 3-(4-fluorophenoxy)-5-pyridin-2-ylthio)pyridin-2-amine for5-bromo-3-(2-fluorophenoxy)pyridin-2-amine in step C.

Example 11(1S)-1-(5-(5-bromo-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-ylamino)-1,2,4-thiazol-3-yl)ethane-1,2-diol

(1S)-1-(5-(5-bromo-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolwas synthesized following the procedure in example 1 substituting5,6,7,8-tetrahydroquinolin-5-ol for 2-methylpyridin-3-ol in step D. M+H(apci)=464, 466.

Example 12(S)-1-(5-(5-bromo-3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol

Step A: POCl₃ (12.9 ml, 141.2 mmol) was added to DMF (10.9 ml, 141.2mmol) at 0° C. The reaction was immediately warmed to ambienttemperature and stirred for 30 minutes.((2,2-diethoxyethoxy)methyl)benzene (10.6 g, 47.1 mmol) was added as asolution in 80 mL of chloroform. The solution was stirred at 75° C. for3.5 hours. The solution was cooled, poured over ice water, andneutralized with Na₂CO₃. The residue was extracted with chloroform andthe organic layer was dried with Na₂SO₄ and concentrated. The residuewas re-dissolved in MeOH (450 mL). NaOMe (25% in MeOH, 58 ml, 253 mmol)was added followed by 2-hydrazinylethanol (10.6 g, 139 mmol). Thereaction stirred overnight at ambient temperature. The material wasconcentrated in vacuo followed by dilution with saturated NH₄Clsolution. The material was extracted with EtOAc, dried (Mg₂SO₄), andconcentrated. Flash chromatography gave2-(4-(benzyloxy)-1H-pyrazol-1-yl)ethanol (1.81 g, 13% yield).

Step B: 2-(4-(benzyloxy)-1H-pyrazol-1-yl)ethanol (1.81 g, 8.3 mmol) wasdissolved in THF (15 mL) under nitrogen. Pd/C (0.22 g, 0.21 mmol) wasadded and the solution was placed under vacuum and charged with ahydrogen balloon. The mixture stirred at ambient temperature overnightunder this hydrogen atmosphere. The solution was filtered through GF/Fpaper and concentrated to give 1-(2-hydroxyethyl)-1H-pyrazol-4-ol (1.8g, quantitative).

Step C:(S)-1-(5-(5-bromo-3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol(APCI POS 443, 445 M+H) was synthesized following the procedure inExample 1 substituting 1-(2-hydroxyethyl)-1H-pyrazol-4-ol for2-methylpyridin-3-ol in Step D.

The following compounds were also prepared according to theabove-described methods.

Example Structure Name M + H 13

(R)-1-(2-(5-bromo-3-(2- methylpyridin-3- yloxy)pyridin-2-ylamino)thiazo-4-yl)ethane- 1,2-diol 424 14

(S)-1-(5-(5-(2- hydroxyethylthio)-3-(pyridin-3-yloxy)pyridin-2-ylamino)- 1,2,4-thiadiazol-3-yl)ethane- 1,2-diol 40815

(S)-1-(5-(5-bromo-3-(1- methyl-1H-pyrazol-4- yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane- 1,2-diol 413, 415 16

(S)-1-(5-(3-(1-methyl-1H- pyrazol-4-yloxy)-5-(2- methylpyridin-3-ylthio)pyridin-2-ylamino)- 1,2,4-thiadiazol-3-yl)ethane- 1,2-diol 458 17

(S)-1-(5-(5-(2-methylpyridin- 3-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin- 2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol 486

The present invention further contemplates the preparation of thefollowing compounds of formula I.

Example Structure  18  18A

D² = CH D² = N  19  19A

D² = CH D² = N  20  20A

D² = CH D² = N  21  21A

D² = CH D² = N  22  22A

D² = CH D² = N  23      23A

D² = CH R = Et, iPr, CH₂OH, CH₂CH₂OH, or CF₃ D² = N R = Et, iPr, CH₂OH,CH₂CH₂OH, or CF₃  24  24A

D² = CH D² = N  25  25A

D² = CH D² = N  26  26A

D² = CH D² = N  27  27A

D² = CH D² = N  28  28A

D² = CH D² = N  29  29A

D² = CH D² = N  30  30A

D² = CH D² = N  31  31A

D² = CH D² = N  32  32A

D² = CH D² = N  33  33A

D² = CH D² = N  34  34A

D² = CH D² = N  35  35A

D² = CH D² = N  36  36A

D² = CH D² = N  37  37A

D² = CH D² = N  38  38A

D² = CH D² = N  39  39A

D² = CH D² = N  40  40A

D² = CH D² = N  41  41A

D² = CH D² = N  42  42A

D² = CH D² = N  43  43A

D² = CH D² = N  44  44A

D² = CH D² = N  45  45A

D² = CH D² = N  46  46A

D² = CH D² = N  47  47A

D² = CH D² = N  48  48A

D² = CH D² = N  49  49A

D² = CH D² = N  50  50A

D² = CH D² = N  51  51A

D² = CH D² = N  52  52A

D² = CH D² = N  53  53A

D² = CH D² = N  54  54A

D² = CH D² = N  55  55A

D² = CH D² = N  56  56A

D² = CH D² = N  57  57A

D² = CH D² = N  58  58A

D² = CH D² = N  59  59A

D² = CH D² = N  60  60A

D² = CH D² = N  61  61A

D² = CH D² = N  62      62A

D² = CH R^(A), R^(B), R^(C) are independently H or Me D² = N R^(A),R^(B), R^(C) are independently H or Me  63      63A

D² = CH R^(A), R^(B), R^(C) are independently H or Me D² = N R^(A),R^(B), R^(C) are independently H or Me  64      64A

D² = CH R^(A), R^(B), R^(C) are independently H or Me D² = N R^(A),R^(B), R^(C) are independently H or Me  65      65A

D² = CH R^(A), R^(B), R^(C) are independently H or Me D² = N R^(A),R^(B), R^(C) are independently H or Me  66      66A

D² = CH R^(A), R^(B), R^(C) are independently H or Me D² = N R^(A),R^(B), R^(C) are independently H or Me  67      67A

D² = CH R^(A), R^(B), R^(C) are independently H or Me D² = N R^(A),R^(B), R^(C) are independently H or Me  68      68A

D² = CH R^(A), R^(B), R^(C) are independently H or Me D² = N R^(A),R^(B), R^(C) are independently H or Me  69      69A

D² = CH R^(A), R^(B), R^(C) are independently H or Me D² = N R^(A),R^(B), R^(C) are independently H or Me  70  70A

D² = CH D² = N  71  71A

D² = CH D² = N  72  72A

D² = CH D² = N  73  73A

D² = CH D² = N  74  74A

D² = CH D² = N  75  75A

D² = CH D² = N  76  76A

D² = CH D² = N  77  77A

D² = CH D² = N  78  78A

D² = CH D² = N  79  79A

D² = CH D² = N  80  80A

D² = CH D² = N  81  81A

D² = CH D² = N  82  82A

D² = CH D² = N  83  83A

D² = CH D² = N  84  84A

D² = CH D² = N  85  85A

D² = CH D² = N  86  86A

D² = CH D² = N  87  87A

D² = CH D² = N  88      88A

D² = CH R = S-pyrid-2-yl, CF₃, S-2- methylpyrid-3-yl D² = N R =S-pyrid-2-yl, CF₃, S-2- methylpyrid-3-yl  89      89A

D² = CH R = S-pyrid-2-yl, CF₃, S-2- methylpyrid-3-yl D² = N R =S-pyrid-2-yl, CF₃, S-2- methylpyrid-3-yl  90      90A

D² = CH R = S-pyrid-2-yl, CF₃, S-2- methylpyrid-3-yl D² = N R =S-pyrid-2-yl, CF₃, S-2- methylpyrid-3-yl  91      91A

D² = CH R = S-pyrid-2-yl, CF₃, S-2- methylpyrid-3-yl D² = N R =S-pyrid-2-yl, CF₃, S-2- methylpyrid-3-yl  92  92A

D² = CH D² = N  93  93A

D² = CH D² = N  94  94A

D² = CH D² = N  95  95A

D² = CH D² = N  96  96A

D² = CH D² = N  97  97A

D² = CH D² = N  98  98A

D² = CH D² = N  99    99A

D² = CH R^(D) = H, Me, or CF₃ D² = N R^(D) = H, Me, or CF₃ 100   100A

D² = CH R^(D) is H, CF₃ or (1-6C alkyl) D² = N R^(D) is H, CF₃ or (1-6Calkyl) 101   101A

D² = CH R^(D) is H, CF₃ or (1-6C alkyl) D² = N R^(D) is H, CF₃ or (1-6Calkyl) 102   102A

D² = CH R^(D) is H, CF₃ or (1-6C alkyl) D² = N R^(D) is H, CF₃ or (1-6Calkyl) 103   103A

D² = CH R^(D) is H, CF₃ or (1-6C alkyl) D² = N R^(D) is H, CF₃ or (1-6Calkyl) 104   104A

D² = CH R^(D) is H, CF₃ or (1-6C alkyl) D² = N R^(D) is H, CF₃ or (1-6Calkyl) 105   105A

D² = CH R^(D) is H, CF₃ or (1-6C alkyl) D² = N R^(D) is H, CF₃ or (1-6Calkyl) 106 106A

D² = CH D² = N 107 107A

D² = CH D² = N 108 108A

D² = CH D² = N 109 109A

D² = CH D² = N 110 110A

D² = CH D² = N 111 111A

D² = CH D² = N 112 112A

D² = CH D² = N 113 113A

D² = CH D² = N 114 114A

D² = CH D² = N 115 115A

D² = CH D² = N 116 116A

D² = CH D² = N 117   117A   117B   117C

D² = CH X² = CH₂ D² =CH₂ X² = O D² = N X² = CH₂ D² =N X² = O 118   118A  118B   118C

D² = CH X² = CH₂ D² = CH₂ X² = O D² = N X² = CH₂ D² = N X² = O 119  119A   119B   119C

D² = CH X² = CH₂ D² = CH₂ X² = O D² = N X² = CH₂ D² = N X² = O 120  120A   120B   120C

D² = CH X² = CH₂ D² = CH₂ X² = O D² = N X² = CH₂ D² = N X² = O 121  121A   121B   121C

D² = CH X² = CH₂ D² = CH₂ X² = O D² = N X² = CH₂ D² = N X² = O 122  122A   122B   122C

D² = CH X² = CH₂ D² = CH₂ X² = O D² = N X² = CH₂ D² = N X² = O 123  123A   123B   123C

D² = CH X² = CH₂ D² = CH₂ X² = O D² = N X² = CH₂ D² = N X² = O 124  124A   124B   124C

D² = CH X² = CH₂ D² = CH₂ X² = O D² = N X² = CH₂ D² = N X² = O 125 125A

D² = CH D² = N 126 126A

D² = CH D² = N 127 127A

D² = CH D² = N 128 128A

D² = CH D² = N 129 129A

D² = CH D² = N 130 130A

D² = CH D² = N 131 131A

D² = CH D² = N 132 132A

D² = CH D² = N 133 133A

D² = CH D² = N

Example 134(S)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride

Step A: To 600 mL of DMF in a 4 neck 3000 mL round bottom flask equippedwith an overhead stir mechanism under nitrogen was added2-methylpyridin-3-ol (71.8 g, 658 mmol) and the reaction cooled to 2° C.60% sodium hydride (26.3 g, 658 mmol) was added at such as rate that theinternal temperature did not exceed 10° C. over a period of 30 minutes.The reaction was stirred while warming to ambient temperature for 1hours. To the reaction was added 5-bromo-3-nitropicolinonitrile (150 g,658 mmol) in a solution of 400 mL of DMF in two portions and thereaction held at ambient temperature for 1.5 hours. To the reaction atambient temperature was added pyridine-2-thiol (73.1 g, 658 mmol) as asolid in portions and the reaction was stirred for 15 minutes todissolve the material. The reaction was cooled to 3° C. and sodiumhydride (26.3 g, 658 mmol) again was added in portions such that theinternal temp did not go above 10° C. (35 minute addition time). Thereaction was removed from the ice bath and warmed to ambient temperaturewhile stirring for 12 hours. The reaction was diluted with 4 volumes (8L) of brine. The mixture was stirred for 30 minutes, at which pointsolid formed. The solid was filtered off and filtrate extracted withMTBE (10 L total). The MTBE phase was concentrated in vacuo. The solidwas combined with concentrated material and dissolved in ethyl acetate(3 L). The EtOAc was washed with brine (4×1 L), dried over MgSO₄,filtered and concentrated in vacuo. The solid that formed was groundinto a powder and dried in vacuo for 4 hours. The material was taken upin 30 mL of MTBE/10 g of product and the reaction was stirred for 30minutes. The solid was filtered and dried in vacuo (2 hours). The solidswere combined and dried for 3 hours in vacuo to yield3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (181 g,85%)

Step B: To concentrated H₂SO₄ (90 mL) cooled in an ice bath was added3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (43 g,130 mmol) in portions such that the internal temp did not exceed 50° C.but did not go below 25° C. After complete addition, the mixture wasstirred in the ice bath until the reaction started to cool, at whichpoint the reaction was removed from the ice bath and the mixture washeated to 50° C. The reaction was cooled to ambient temperature andslowly added to ice water over 3 minutes (about 1400 mL of 30% ice inwater). The mixture was further cooled in an ice bath to 5° C. andneutralized to pH ˜10 with 4M NaOH (about 800 mL) while keeping theinternal temperature below 20° C., at which point a solid formed. Themixture was stirred for 20 minutes. The mixture was filtered and washedwith MTBE (5×150 mL), hexanes (×100 mL), and dried at under vacuum toafford 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (43g, 96%).

Step C: To a 3-neck 2 L round bottom flask was added 2M aqueous sodiumhydroxide (343 ml, 686 mmol) and the solution was cooled in an ice bath.Bromine (12 ml, 257 mmol) was added and the mixture was stirred for 30minutes while the ice bath was removed.3-(2-Methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (58 g, 171mmol) was added as a slurry in about 600 mL of dioxane in 1 portion.After 30 minutes, concentrated HCl was added in 1 mL portions to a pH˜1. The reaction was stirred for 15 minutes and 4N NaOH was added to thesolution to pH ˜10. The aqueous mixture was extracted with EtOAc (3×750mL), washed with water (2×250 mL) and brine (300 mL), dried over MgSO₄,filtered and concentrated. The material was dried in vacuo at 50° C. atwhich point a red solid formed. The solid was triturated with CH₂Cl₂(about 40 mL of CH₂Cl₂ to 5 g of material) and the solid filtered. Thesolid was washed with CH₂Cl₂ and dried under vacuum at 50° C. Thefiltrate was concentrated in vacuo and material purified over silica gel(3% MeOH/CH₂Cl₂) to afford a red solid. The two crops were combined toafford 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine(24 g, 45%).

Step D: To 1000 mL of DI water was added hydroxyl amine hydrochloride(51.0 g, 734 mmol) and the mixture was stirred for 5 minutes. Sodiumcarbonate (38.1 g, 360 mmol) was added in 3 large portions and thereaction was stirred for 15 minutes. THF (700 mL) was added to thereaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734mmol) was added in 1 portion in 800 mL of THF. The reaction was stirredfor 4 hours and poured into a 4 L separatory funnel and the layersseparated. The aqueous layer was extracted twice with MTBE (about 3000mL total). The combined organic layers were washed with water (700 mL)and brine (300 mL), dried over MgSO₄, and concentrated in vacuo toafford (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%)as a clear oil.

Step E: To a 4-neck 2 L round bottom flask was added(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135.1 g, 729.4 mmol)and 750 mL of DMF. The reaction was placed in a water bath and1-chloropyrrolidine-2,5-dione (97.40 g, 729.4 mmol) was added inportions over 2 minutes. The reaction was stirred in the water bath for3 hours, then diluted with 2 L of MTBE and washed with 1 L of water. Thewater was extracted with 500 mL of MTBE. The combined organic layerswere washed with water (5×800 mL) and brine (300 mL), dried over MgSO₄and concentrated in vacuo to afford added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,98%) as a green viscous oil.

Step F: In a 4 neck 5 L flask was added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,719 mmol) in 2.5 L of THF. The material was cooled to 3° C. andmethanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portionsover 10 minutes. N-ethyl-N-isopropylpropan-2-amine (126 ml, 719 mmol)was added through an addition funnel over 12 minutes. The reaction wasstirred in the ice bath for 30 minutes and then at ambient temperaturefor 1 hour. The reaction was filtered and the solids washed with MTBE(about 3 L). The filtrate was concentrated and the residue was purifiedover silica gel (7:1 to 3:1 Hexanes/EtOAc) to afford an oil that slowlysolidified under vacuum. The solids were ground using a mortar andpestle, washed with hexanes (about 1000 mL) and dried to afford(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (158 g, 531 mmol, 73.8% yield) as a white solid.

Step G: To 700 mL of acetonitrile was added sodium isothiocyanate (12.5g, 155 mmol), pyridine (25.2 ml, 309 mmol) and(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (38.4 g, 129 mmol) and the reaction heated to 60° C. for 15minutes (white solid formed). To the mixture was added3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (32 g,103 mmol) as a solid and the reaction was stirred for 14 hours at 60° C.The reaction was cooled and concentrated in vacuo. The residue waspartitioned between EtOAc and 1N NaOH. The aqueous mixture (basic, about700 ML) was extracted twice with EtOAc (3000 mL total volume). Thecombined organic layers were washed with 1 N NaOH (300 mL) and brine(300 mL), dried over MgSO₄ and concentrated in vacuo. The residue waspurified by chromatography on about 1 kg of silica gel using 1:1EtOAc/CH₂Cl₂ with 1% MeOH as eluent to afford(S)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(38.7 g, 72.4 mmol, 70.2% yield).

Step H: In 1 L of absolute ethanol was added(S)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl-1,2,4-thiadiazol-5-amine(41 g, 76.7 mmol) and the reaction was heated to 80° C. 41 mL of aqueousHCl (11.6 mL of concentrated HCl diluted in water) was added. After 2hours, the resultant solid material was hot filtered, washed withethanol (200 mL) and dried in vacuo to yield crude product as a solidwhich contained about 2% starting material. The solids were suspended inEtOH (1 L) and heated to 80° C. followed by 41 mL of aqueous HCl (11.6mL of concentrated HCl diluted in water). After 3.5 hours the resultantsolid material was hot filtered, washed with ethanol (200 mL) and driedin vacuo and to afford(S)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride (35 g, 85%). Mass Spectrum (apci) m/z=455.2 (M+H—HCl).

Example 135(S)-1-(5-(3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride

Step A: To a 0° C. solution of 2,6-dimethylpyridin-3-ol (10 g, 81.2mmol) in DMF (50 ml) was added sodium hydride (60% dispersion in oil,3.4 g, 85 mmol). After 15 minutes, 5-bromo-3-nitropicolinonitrile (18.5g, 81 mmol) was added and the mixture was allowed to warm slowly toambient temperature. The reaction mixture was slowly added to 500 mL ofrapidly stirring water. A light red solid formed and then the materialformed a gum. The gum was extracted into ethyl acetate, and the organicswashed with brine, dried over MgSO₄ and concentrated in vacuo to afford5-bromo-3-(2,6-dimethylpyridin-3-yloxy)picolinonitrile (25 g, 82 mmol,101% yield).

To 5-bromo-3-(2,6-dimethylpyridin-3-yloxy)picolinonitrile (25 g, 82mmol) was added concentrated sulfuric acid (25 ml) and the mixturestirred at ambient temperature over night. The mixture was poured ontoice (500 ml) and the aqueous mixture neutralized using 50% NaOH. A solidformed at pH 7. The solid was collected and dried in vacuo to afford3-(2,6-dimethylpyridin-3-yloxy)-5-bromopicolinamide (24.2 g, 92%).

To a 0° C. solution of NaOH (150 mL, 2M) was added bromine (14.4 g, 90mmol), followed by 3-(2,6-dimethylpyridin-3-yloxy) 5-bromopicolinamide(24 g, 75 mmol) dissolved in dioxanes (300 ml). The reaction was stirredat ambient temperature for 1 hour and then at 80° C. for 1 hour. Thereaction was cooled to ambient temperature and acidified to pH 1 withconcentrated HCl. The mixture was stirred at ambient temperature for 1hour and basified to pH 10 using 2M NaOH. The aqueous layer wasextracted into ethyl acetate. The combined organic layers were washedwith brine, dried over MgSO₄ and concentrated in vacuo to afford5-bromo-3-(2,6-dimethylpyridin-3-yloxy)pyridin-2-amine (20.5 g, 92%).

Step D: A 250 mL flask was charged with5-bromo-3-(2,6-dimethylpyridin-3-yloxy)pyridin-2-amine (5.00 g, 17.66mmol) and THF (100 mL) and purged with nitrogen. The solution was cooledto −78° C., methyl lithium (1.6 M in hexanes, 12.7 mL, 20.4 mmol) wasadded and the reaction was stirred for 5 minutes. Butyl lithium (2.5 Min Hexanes, 8.1 mL, 20.4 mmol) was added and the reaction was stirredfor 10 minutes at −78° C. (solids formed).2-(2-(Pyridin-3-yl)disulfanyl)pyridine (4.49 g, 20.4 mmol) was added andthe reaction was warmed to ambient temperature and stirred for 18 hours.The reaction was poured into aqueous NH₄Cl, extracted with EtOAc, washedwith brine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified over silica gel (5% MeOH in CH₂Cl₂) to afford3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (3.5g, 63%).

Step E: In 1000 mL of DI water was added hydroxyl amine hydrochloride(51.0 g, 734 mmol) and the reaction was stirred for 5 minutes. Sodiumcarbonate (38.1 g, 360 mmol) was added in 3 large portions and thereaction was stirred for 15 minutes. THF (700 mL) was added to thereaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734mmol) was added in 1 portion in 800 mL of THF. The reaction was stirredfor 4 hours and poured into a 4 L separatory funnel and the layersseparated. The aqueous layer was extracted twice with MTBE (about 3000mL total). The combined organic layers were washed with water (700 mL)and brine (300 mL), dried over MgSO₄ and concentrated in vacuo to afford(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%) as aclear viscous oil.

Step F: To a 4-neck 2 L round bottom flask was added(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135.1 g, 729.4 mmol)and dissolved in 750 mL of DMF. The reaction was placed in a water bathand 1-chloropyrrolidine-2,5-dione (97.40 g, 729.4 mmol) was added inportions over 2 minutes. The reaction was stirred in the water bath for3 hours, then diluted with 2 L of MTBE and washed with 1 L of water. Thewater was extracted with 500 mL of MTBE. The combined organic layerswere washed with water (5×800 mL) and brine (300 mL), dried over MgSO₄and concentrated in vacuo to afford added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,98%) as a green viscous oil.

Step G: In a 4 neck 5 L flask was added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,719 mmol) in 2.5 L of THF. The material was cooled to 3° C. andmethanesulfonyl chloride (56.1 ml, 719 mmol) was added through anaddition funnel over 12 minutes. The reaction was filtered and thesolids washed with MTBE (about 3 L). The filtrate was concentrated andthe residue was purified over silica gel (7:1 to 3:1 Hex/EtOAc) toafford an oil that slowly solidified under vacuum. The solids wereground using a mortar and pestle, washed with hexanes (about 1000 mL)and dried to afford(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (158 g, 531 mmol, 73.8% yield) as a white solid.

Step H: To a solution of sodium isothiocyanate (0.24 g, 3.0 mmol) inacetonitrile (30 mL) was added pyridine (0.51 g, 6.5 mmol) followed by(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (0.77 g, 2.6 mmol) and the reaction was stirred at 60° C. for20 minutes, followed by addition of3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine(0.70 g, 2.2 mmol) and the reaction was stirred overnight at 60° C. Thereaction was concentrated in vacuo and the residue partitioned betweenEtOAc and 2 M NaOH. The combined organic layers were washed with brine,dried over MgSO₄ and concentrated in vacuo. The material was purifiedover silica gel (30% EtOAc in CH₂Cl₂) to afford(S)-N-(3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl-1,2,4-thiadiazol-5-amine(0.50 g, 0.91 mmol, 42% yield).

Step I: To a solution of(S)-N-(3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.70 g, 1.3 mmol) in ethanol (20 mL) was added concentrated HCl (2.4ml) and the reaction was heated to 80° C. for 2 hours. The reaction wasconcentrated and the material triturated with EtOH. The solid wasfurther purified by reverse phase HPLC to yield pure product. Theproduct was taken up in ethanol and HCl (2M in ether) was added. Themixture was stirred for 2 hours and concentrated in vacuo and dried invacuo to yield the product as the HCl salt (73.2 mg, 12%). Mass Spectrum(apci) m/z=469.2 (M+H—HCl).

Example 136(S)-1-(5-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride

Step A: To a solution of 2-methylpyridin-3-ol (11.8 g, 108 mmol) in DMFat 0° C. was added sodium hydride (60% dispersion in oil, 4.32 g, 108mmol) in small portions and the reaction was warmed to ambienttemperature. To this mixture was added 5-bromo-3-nitropicolinonitrile(24.6 g, 108 mmol) and the reaction was stirred overnight at ambienttemperature. The reaction was poured into water (1000 mL) and theaqueous layer extracted with EtOAc. The combined organic layers werewashed with water (3×) and brine, dried over MgSO₄ and concentrated invacuo to yield 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g,48%).

Step B: To 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g, 52mmol) was added concentrated H₂SO₄ (30 mL) and the slurry was left tostir overnight, at which point the material was fully dissolved. Thereaction was poured into 0° C. water in small portions. Whilemaintaining the temp below 20° C., the aqueous layer was basified by theaddition of NaOH pellets, to a pH of ˜5, at which point a solid formed.The solid was filtered and the remaining aqueous layer was extractedwith EtOAc. The organic layers, combined with the solid, were washedwith brine, dried over MgSO₄ and concentrated in vacuo to yield5-bromo-3-(2-methylpyridin-3-yloxy)picolinamide (11 g, 69%).

Step C: To a solution of NaOH (2M, 90 mL, 182 mmol) at 0° C. was addedbromine (8.71 g, 54 mmol) and the reaction was stirred at 0° C. for 30minutes. To this mixture was added5-bromo-3-(2-methylpyridin-3-yloxy)picolinamide (11.2 g, 36.3 mmol) indioxanes (100 mL) and the reaction was stirred at ambient temperaturefor 1 hour followed by heating to 80° C. for 1 hour. The reaction wascooled to ambient temperature and acidified to pH 1 using concentratedHCl. The reaction was basified and a solid precipitated. The solid wasfiltered and dried in vacuo to yield5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (4.1 g, 41%).

Step D: In 1000 mL of DI water was added hydroxyl amine hydrochloride(51.0 g, 734 mmol) and the reaction was stirred for 5 minutes. Sodiumcarbonate (38.1 g, 360 mmol) was added in 3 large portions and thereaction was stirred for 15 minutes. THF (700 mL) was added to thereaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734mmol) in 800 mL of THF was added in 1 portion. The reaction was stirredfor 4 hours, then poured into a 4 L separatory funnel. The layersseparated and the aqueous layer was extracted twice with MTBE (about3000 mL total). The combined organic layers were washed with water (700mL) and brine (300 mL), dried over MgSO₄, and concentrated in vacuo toafford (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%)as a clear viscous oil.

Step E: To a 4-neck 2 L round bottom flask was added(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135.1 g, 729.4 mmol)dissolved in 750 mL of DMF. The reaction was placed in a water bath and1-chloropyrrolidine-2,5-dione (97.40 g, 729.4 mmol) was added inportions over 2 minutes. The reaction was stirred in the water bath for3 hours. The reaction was diluted with 2 L of MTBE and washed with 1 Lof water. The water was extracted with 500 mL of MTBE. The combinedorganic layers were washed with water (5×800 mL) and brine (300 mL),dried over MgSO₄ and concentrated in vacuo to afford added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,98%) as a green viscous oil.

Step F: In a 4 neck flask was added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,719 mmol) in 2.5 L of THF. The material was cooled to 3° C. andmethanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portionsover 10 minutes. Next, N-ethyl-N-isopropylpropan-2-amine (126 ml, 719mmol) was added through an addition funnel over 12 minutes. The reactionwas stirred in the ice bath for 30 minutes and then at ambienttemperature for 1 hour. The reaction was filtered and the solids washedwith MTBE (about 3 L). The filtrate was concentrated and the residue waspurified over silica gel (3 kg silica, 7:1 to 3:1 Hex/EtOAc) to affordan oil that slowly solidified under vacuum. The solids were ground usinga mortar and pestle and washed with hexanes (about 1000 mL) and dried toafford (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (158 g, 531 mmol, 73.8% yield) as a white solid.

Step G: In 100 mL of acetonitrile was added sodium thioisocyanate (1.5g, 20 mmol), pyridine (3.5 g, 44 mmol), followed by(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (5.2 g, 18 mmol) and the reaction was heated to 60° C. for 30minutes. 5-Bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (4.1 g, 15mmol) was added and the reaction was heated overnight at 60° C. Thereaction was concentrated to one fourth the volume and the residuepartitioned between EtOAc and water made basic with 1N NaOH. The organiclayer was separated and the aqueous layer extracted with EtOAc. Thecombined organic layers were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The material was purified on silica gel (25%EtOAc in CH₂Cl₂) to afford(S)-N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(5.4 g, 73%).

Step H: To a solution of(S)-N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(3.1 g, 6.14 mmol) in dioxanes (30 mL) continuously purged with nitrogenwas added Xanphos (0.177 g, 0.303 mmol), Pd₂dba₃ (0.14 g, 0.153 mmol),methyl 3-mercaptopropanoate (0.73 g, 6.14 mmol) andN,N-diisopropylethylamine (1.17 mL, 6.45 mmol) and the reaction heatedovernight at 80° C. The reaction was concentrated in vacuo and theresidue purified over silica gel (5% MeOH/CH₂Cl₂) to afford (S)-methyl3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate(2.3 g, 68%).

Step I: To a solution of (S)-methyl3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate(0.428 g, 0.787 mmol) in THF (20 mL) was added potassium2-methylpropan-2-olate (1M in THF, 2.36 ml, 2.36 mmol) and the reactionwas stirred at ambient temperature for 5 minutes.(Bromomethyl)cyclopropane (0.106 g, 0.787 mmol) was added followed byDMF (5 mL) and the reaction was stirred for 1 hour at ambienttemperature. The reaction was poured into EtOAc (500 mL) and the organiclayer was washed with a 1:1 solution of water, 1N NaOH (100 mL total)and brine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified over silica gel (40% EtOAc/CH₂Cl₂) to afford(S)-N-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.30 g, 0.586 mmol, 74.5% yield).

Step J: To a solution of(S)-N-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.30 g, 0.586 mmol) in ethanol (20 mL) was added 1 M HCl (0.87 mL) andthe reaction heated to 80° C. for 2 hours. The reaction was cooled andconcentrated in vacuo and the solid triturated with ethanol. The solidwas dried in vacuo to afford(S)-1-(5-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol(0.146 g, 0.338 mmol, 57.7% yield) as the mono HCl salt. Mass Spectrum(apci) m/z=432.0 (M+H—HCl).

Example 137(S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol

Step A: 2-Bromopyridin-3-yl acetate (10 g, 46 mmol) was dissolved in THF(80 mL) and triethylamine (32 ml, 231 mmol), ethynyltrimethylsilane(19.5 ml, 139 mmol), and CuI (0.44 g, 2.3 mmol) were added. The mixturewas degassed with argon for 15 minutes, then PdCl₂(PPh₃)₂ (1.6 g, 2.3mmol) was added and the mixture was stirred under argon at ambienttemperature for 18 hours. The reaction was concentrated in vacuo,dissolved in 25% EtOAc in hexanes, filtered and purified over silica gel(25% ethyl acetate/hexanes) to afford2-((trimethylsilyl)ethynyl)pyridin-3-yl acetate (9.7 g, 41 mmol).

Step B: To a solution of 2-((trimethylsilyl)ethynyl)pyridin-3-yl acetate(9.5 g, 41 mmol) in THF (200 mL) was added water (25 ml). The reactionwas cooled to 0° C. and TBAF (1M, 45 ml, 45 mmol) was added. The mixturewarmed to ambient temperature and stirred for 1 hour. Water (100 mL) wasadded and the volume was reduced by half. The product was extracted intoether (3×100 mL), washed with brine and dried over MgSO₄. The solutionwas concentrated in vacuo to afford 2-ethynylpyridin-3-yl acetate (5.5g, 34 mmol) as a light brown oil.

Step C: To a solution of 2-ethynylpyridin-3-yl acetate (5.0 g, 31 mmol)in ethanol (50 mL) was added PtO₂ (0.50 g, 2.2 mmol). The mixture wasdegassed with nitrogen and placed under a double-layer balloon ofhydrogen. The reaction was stirred at ambient temperature for 30minutes, then filtered and concentrated in vacuo to give2-ethylpyridin-3-yl acetate (5.1 g, 31 mmol) which was used in the nextstep without further purification.

Step D: To a solution of 2-ethylpyridin-3-yl acetate (5.1 g, 31 mmol) inethanol (50 mL) was added 3M LiOH (50 mL, 150 mmol). The reactionmixture stirred at ambient temperature for 30 minutes. The mixture wasconcentrated to dryness and purified over silica gel (10% MeOH inCH₂Cl₂) to afford 2-ethylpyridin-3-ol (2.5 g, 20 mmol).

Step E: To a solution of 2-ethylpyridin-3-ol (2.5 g, 20.3 mmol) in DMF(20 ml) at 0° C. was added sodium hydride (0.512 g, 21.3 mmol). After 15minutes, 5-bromo-3-nitropicolinonitrile (4.63 g, 20.3 mmol) was addedand the mixture was allows to warm slowly to ambient temperature andstirred for 2 hours. Pridine-2-thiol (0.804 g, 7.23 mmol) was addedfollowed by sodium hydride (0.182 g, 7.60 mmol) and the mixture wasstirred at ambient temperature overnight. Water (200 ml) was added andthe mixture was extracted with diethyl ether (3×100 mL), washed withbrine, dried over MgSO₄, filtered and concentrated in vacuo. The residuewas purified over silica gel (25 to 75% EtOAc in Hexanes) to afford3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (1.4 g,4.19 mmol).

Step F: 3-(2-Ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile(1.4 g, 4.19 mmol) was stirred in concentrated sulfuric acid (10 mL)overnight at ambient temperature. Ice (100 g) was added and the solutionwas neutralized using 4M NaOH. Ice was added as necessary to maintainthe temperature below 20° C. The product was extracted into ethylacetate, washed with brine, dried over MgSO₄, filtered and concentratedto afford 3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide(1.5 g, 4.2 mmol).

Step G: A 1M solution of NaOH (10.6 ml, 21.2 mmol) was cooled to 0° C.and bromine (0.38 ml, 7.4 mmol) was added. This mixture stirred atambient temperature for 30 minutes. Dioxane (15 mL) was added followedby 3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (1.50 g,4.25 mmol). The mixture stirred at ambient temperature for 30 minutes.Concentrated HCl was added until the solution was pH 1 and the mixturestirred for 5 minutes. The reaction was made basic with 1M NaOH and theproduct was extracted into ethyl acetate (3×100 mL). The combinedorganic layers were washed with brine and dried over MgSO₄. The solutionwas concentrated and purified over silica gel (50 to 100% EtOAc inHexanes) to afford3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (0.620 g,1.91 mmol).

Step H: In 1000 mL of DI water was added hydroxyl amine hydrochloride(51.0 g, 734 mmol) and the reaction was stirred for 5 minutes. Sodiumcarbonate (38.1 g, 360 mmol) was added in 3 large portions and thereaction was stirred for 15 minutes. THF (700 mL) was added to thereaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734mmol) was added in 1 portion in 800 mL of THF. The reaction was stirredfor 4 hours, then poured into a 4 L separatory funnel and the layersseparated. The aqueous layer was extracted twice with MTBE (about 3000mL total). The combined organic layers were washed with water (700 mL)and brine (300 mL), dried over MgSO₄ and concentrated in vacuo to afford(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%) as aclear viscous oil.

Step I: To a 4-neck 2 L round bottom flask was added(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135.1 g, 729.4 mmol)and 750 mL of DMF. The reaction was placed in a water bath and1-chloropyrrolidine-2,5-dione (97.40 g, 729.4 mmol) was added inportions over 2 minutes. The reaction was stirred in the water bath for3 hours. The reaction was diluted with 2 L of MTBE and washed with 1 Lof water. The water was extracted with 500 mL of MTBE, and the combinedorganic layers were washed with water (5×800 mL) and brine (300 mL),dried over MgSO₄ and concentrated in vacuo to afford added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,98%) as a green viscous oil.

Step J: To a 4 neck 5 L flask was added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,719 mmol) in 2.5 L of THF. The material was cooled to 3° C. andmethanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portionsover 10 minutes. Next, N-ethyl-N-isopropylpropan-2-amine (126 ml, 719mmol) was added through an addition funnel over 12 minutes. The reactionwas stirred in the ice bath for 30 minutes and then at ambienttemperature for 1 hour. The reaction was filtered and the solids washedwith MTBE (about 3 L). The filtrate was concentrated and the residue waspurified by chromatography (3 kg silica, 7:1 to 3:1 Hex/EtOAc) to affordan oil that slowly solidified under vacuum. The solids were ground usinga mortar and pestle, washed with hexanes (about 1000 mL) and dried toafford (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (158 g, 531 mmol, 73.8% yield) as a white solid.

Step K:(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (0.854 g, 2.87 mmol), pyridine (0.618 ml, 7.64 mmol), andsodium thiocyanate (0.310 g, 3.82 mmol) were dissolved in acetonitrile(10 mL). The solution was heated to 60° C. for 30 minutes.3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (0.620 g,1.91 mmol) was added and the reaction was heated at 60° C. overnight.The solution was quenched with saturated aqueous NaHCO₃ solution,extracted with EtOAc (3×100 mL), washed with brine, dried over MgSO₄,and concentrated. The material was purified over silica gel (25 to 100%ethyl acetate in hexanes) to afford(S)-N-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.600 g, 1.09 mmol).

Step L:(S)-N-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.600 g, 1.09 mmol) was dissolved in ethanol (25 ml) and water (600 mg)and concentrated HCl (600 mg) were added. The mixture was heated toreflux for 2 hours, concentrated in vacuo, dissolved and concentratedwith EtOH (2×50 mL). The material was triturated from acetonitrile toafford(S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol(0.420 g, 0.90 mmol, 82%) as a solid. Mass Spectrum (apci) m/z=469.1(M+H—HCl).

Example 138(S)-1-(5-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride

Step A: To a solution of 2-methylpyridin-3-ol (11.8 g, 108 mmol) in DMFat 0° C. was added sodium hydride (60% dispersion in oil, 4.32 g, 108mmol) in small portions and the reaction warmed to ambient temperature.To this mixture was added 5-bromo-3-nitropicolinonitrile (24.6 g, 108mmol) and the reaction was stirred overnight at ambient temperature. Thereaction was poured into water (1000 mL) and the aqueous layer extractedwith EtOAc. The combined organic layers were washed with water andbrine, dried over MgSO₄ and concentrated in vacuo to yield5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g, 48%).

Step B: To 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g, 52mmol) was added concentrated H₂SO₄ (30 mL) and the slurry was stirredovernight, at which point the material was fully dissolved. The reactionwas poured into 0° C. water in small portions. While maintaining thetemp below 20° C., the aqueous layer was basified to about a pH of 5 bythe addition of NaOH pellets, at which point a solid formed. The solidwas filtered, and the remaining aqueous layer was extracted with EtOAc.The organics layers, combined with the solid, were washed with brine,dried over MgSO₄ and concentrated in vacuo to yield5-bromo-3-(2-methylpyridin-3-yloxy)picolinamide (11 g, 69%).

Step C: To a solution of NaOH (2M, 90 mL, 182 mmol) at 0° C. was addedbromine (8.71 g, 54 mmol) and the reaction was stirred at 0° C. for 30minutes. To this mixture was added5-bromo-3-(2-methylpyridin-3-yloxy)picolinamide (11.2 g, 36.3 mmol) indioxanes (100 mL) and the reaction was stirred at ambient temperaturefor 1 hour followed by heating to 80° C. for 1 hour. The reaction wascooled to ambient temperature and acidified to pH 1 using concentratedHCl. The reaction was basified and a solid precipitated. The solid wasfiltered and dried in vacuo to yield product5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (4.1 g, 41%).

Step D: In 1000 mL of DI water was added hydroxyl amine hydrochloride(51.0 g, 734 mmol) and the reaction was stirred for 5 minutes. Sodiumcarbonate (38.1 g, 360 mmol) was added in 3 large portions and thereaction was stirred for 15 minutes. THF (700 mL) was added to thereaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734mmol) was added in 1 portion in 800 mL of THF. The reaction was stirredfor 4 hours and poured into a 4 L separatory funnel and the layersseparated. The aqueous layer was extracted twice with MTBE (about 3000mL total). The combined organic layers were washed with water (700 mL)and brine (300 mL), dried over MgSO₄, and concentrated in vacuo toafford (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%)as a clear viscous oil.

Step E: To a 4-neck 2 L round bottom flask was added(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135.1 g, 729.4 mmol)dissolved in 750 mL of DMF. The reaction was placed in a water bath and1-chloropyrrolidine-2,5-dione (97.40 g, 729.4 mmol) was added inportions over 2 minutes. The reaction was stirred in the water bath for3 hours, then diluted with 2 L of MTBE and washed with 1 L of water. Thewater was extracted with 500 mL of MTBE. The combined organic layerswere washed with water (5×800 mL) and brine (300 mL), dried over MgSO₄and concentrated in vacuo to afford added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,98%) as a green viscous oil.

Step F: In a 4 neck 5 L flask was added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,719 mmol) in 2.5 L of THF. The material was cooled to 3° C. andmethanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portionsover 10 minutes. Next, N-ethyl-N-isopropylpropan-2-amine (126 ml, 719mmol) was added through an addition funnel over 12 minutes. The reactionwas stirred in the ice bath for 30 minutes and then at ambienttemperature for 1 hour. The reaction was filtered and the solids washedwith MTBE (about 3 L). The filtrate was concentrated and the residue waspurified over silica gel (3 kg silica, 7:1 to 3:1 Hexane/EtOAc) toafford an oil that slowly solidified under vacuum. The solids wereground using a mortar and pestle, washed with hexanes (about 1000 mL)and dried to afford(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (158 g, 531 mmol, 73.8% yield) as a white solid.

Step G: In 100 mL of acetonitrile was added sodium thioisocyanate (1.5g, 20 mmol), pyridine (3.5 g, 44 mmol), followed by(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (5.2 g, 18 mmol) and the reaction was heated to 60° C. for 30minutes. 5-Bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (4.1 g, 15mmol) was added and the reaction was heated overnight at 60° C. Thereaction was concentrated to about one quarter volume, the residue waspartitioned between EtOAc and the water layer was made basic with 1NNaOH. The organic layer was separated and the aqueous layer extractedwith EtOAc. The combined organic layers were washed with brine, driedover MgSO₄ and concentrated in vacuo. The material was purified onsilica gel (25% EtOAc in CH₂Cl₂) to afford(S)-N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(5.4 g, 73%).

Step H: To a solution of(S)-N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(3.1 g, 6.14 mmol) in dioxanes (30 mL) continuously purged with nitrogenwas added Xanphos (0.177 g, 0.303 mmol), Pd₂dba₃ (0.14 g, 0.15 mmol),methyl 3-mercaptopropanoate (0.73 g, 6.14 mmol) andN,N-diisopropylethylamine (1.17 mL, 6.45 mmol) and the reaction washeated overnight at 80° C. The reaction was concentrated in vacuo andthe residue purified over silica gel (5% MeOH/CH₂Cl₂) to afford(S)-methyl3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate(2.3 g, 68%).

Step I: (S)-Methyl3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate(105 mg, 0.19 mmol) was dissolved in THF (5 ml) and KOtBu (65 mg, 0.58mmol) was added. The mixture was agitated for 30 minutes and1-bromo-3-methoxypropane (37 mg, 0.24 mmol) was added. The mixture wasagitated for 1 hour, diluted with ethyl acetate, washed with sodiumbicarbonate solution and brine, dried over sodium sulfate, filtered andevaporated. The residue was purified over silica gel (60-75% ethylacetate/hexanes) to afford(S)-N-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(85 mg, 83% yield) as glassy colorless solid.

Step J:(S)-N-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(85 mg, 0.16 mmol) was dissolved in ethanol (5 ml) and 1M HCl (0.5 ml)was added. The mixture was heated to 70° C. and agitated 3 hours. Uponcooling, the reaction was diluted with ethyl acetate, basified withsodium carbonate solution and washed with water and brine, dried(MgSO₄), filtered and evaporated. The resulting solid was dissolved insmall amount of dichloromethane and treated with 1M HCl in ether. Afterevaporation,(S)-1-(5-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride (65 mg, 90% yield) was obtained as white solid. MassSpectrum (apci) m/z=450.1 (M+H—HCl).

Example 139(S)-1-(5-(3-(1-Ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride

Step A: In 1 L glass beaker, ethylhydrazine oxalate (51.4 g, 342 mmol)was combined with water (300 ml). To the resulting slurry was added a50% w/v NaOH solution (75.5 g) to adjust the pH to 9.5 (by pH-meter).The mixture was heated to 40° C. and methyl trans-3-methoxyacrylate(24.5 ml, 228 mmol) was added dropwise over 1 hour. The pH was adjustedperiodically to 9.0-9.5 range by addition of 50% w/v NaOH solution.After the completion of addition, the mixture was agitated foradditional 3 hours at 40° C. and the pH was adjusted occasionally toabout 9.0-9.5. The mixture was cooled to 5° C. and filtered. Thefiltrate was evaporated to about 150 ml, cooled to 5° C. and filteredagain. The filtrate was acidified to pH 3-4 with 6M HCl (45 ml) andextracted 8 times with 3:1 mixture of chloroform/isopropanol. Thecombined extracts were dried (MgSO₄), filtered and evaporated. The crudeproduct was purified over silica gel (20% MeOH/EtOAc) to afford1-ethyl-1H-pyrazol-5-ol (18.3 g, 71% yield) as a yellow solid.

Step B: 5-Bromo-3-nitropicolinonitrile (24.0 g, 105 mmol),1-ethyl-1H-pyrazol-5-ol (13.0 g, 116 mmol), and sodium carbonate (11.2g, 105 mmol) were combined with acetonitrile (400 ml). The mixture washeated to reflux for 20 hours, then cooled to ambient temperature,filtered and evaporated. The residue was dissolved in ethyl acetate (800ml) and washed with water (3×200 ml) and brine, dried (MgSO₄), filteredand evaporated. The crude material was purified over silica gel(15:35:50, then 20:30:50 ethyl acetate/chloroform/hexane) to afford5-bromo-3-(1-ethyl-1H-pyrazol-5-yloxy)picolinonitrile (16.4 g, 53%yield) as a white solid.

Step C: 5-Bromo-3-(1-ethyl-1H-pyrazol-5-yloxy)picolinonitrile (16.1 g,55 mmol) and cesium carbonate (17.9 g, 55 mmol) were combined with DMF(160 ml) and pyridin-2-thiol (6.1 g, 55 mmol) dissolved in DMF (40 ml)was added dropwise over 30 minutes. The mixture was agitated for 1 hour,quenched with saturated ammonium chloride solution and extracted withethyl acetate. The combined organic extracts were washed with water andbrine, dried (MgSO₄), filtered and evaporated. The residue was purifiedover silica gel (20-35% ethyl acetate/hexanes) to afford3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (16.6g, 93% yield) as a white solid.

Step D:3-(1-Ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (16.6g, 51.33 mmol) was cooled to −10° C. and concentrated HCl (120 ml, 1440mmol) cooled to the same temperature was added slowly. The mixture wasagitated in the cooling bath until the solids were mostly dissolved (30minutes). The bath was removed and the mixture was agitated for 24hours. The mixture was then cooled to −10° C. and a mixture of ice (150g) and 50% w/v NaOH (120 ml) was added slowly, keeping the temperaturebelow 20° C., to adjust the pH to about 12-13. The mixture was thenextracted twice with dichloromethane and the combined organic extractswere washed with sodium bicarbonate solution, dried (MgSO₄), filteredand evaporated to afford3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinamide (16.5 g,94% yield) as thick amber oil which later solidified.

Step E: A 3 M solution of KOH (15.99 ml, 47.98 mmol) was chilled in a 0°C. bath, bromine (0.5120 ml, 9.996 mmol) was added in one portion andthe mixture was stirred 15 minutes. A solution of3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinamide (1.365g, 3.998 mmol) dissolved in dioxane (10 ml) was added, and the resultingmixture was stirred overnight at ambient temperature. The majority ofthe dioxane was removed in vacuo and the resulting aqueous mixture wasextracted with EtOAc. The organic extract was washed with water, driedover Na₂SO₄, filtered and concentrated to afford crude3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (1.12g, 3.574 mmol, 89.39% yield) (82% Product and 18% starting material byLC.). The crude product was carried directly onto the next step withoutfurther purification.

Step F: In 1000 mL of DI water was added hydroxyl amine hydrochloride(51.0 g, 734 mmol) and the reaction was stirred for 5 minutes. Sodiumcarbonate (38.1 g, 360 mmol) was added in 3 large portions and thereaction was stirred for 15 minutes. THF (700 mL) was added to thereaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734mmol) was added in 1 portion in 800 mL of THF. The reaction was stirredfor 4 hours and poured into a 4 L separatory funnel and the layersseparated. The aqueous layer was extracted twice with MTBE (about 3000mL total). The combined organic layers were washed with water (700 mL)and brine (300 mL), dried over MgSO₄, and concentrated in vacuo toafford (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%)as a clear viscous oil.

Step G: To a 4-neck 2 L round bottom flask was added(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135.1 g, 729.4 mmol)dissolved in 750 mL of DMF. The reaction was placed in a water bath and1-chloropyrrolidine-2,5-dione (97.40 g, 729.4 mmol) was added inportions over 2 minutes. The reaction was stirred in the water bath for3 hours, then diluted with 2 L of MTBE and washed with 1 L of water. Thewater was extracted with 500 mL of MTBE. The combined organic layerswere washed with water (5×800 mL) and brine (300 mL), dried over MgSO₄and concentrated in vacuo to afford added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,98%) as a green viscous oil.

Step H: In a 4 neck 5 L flask was added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,719 mmol) in 2.5 L of THF. The material was cooled to 3° C. andmethanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portionsover 10 minutes. Next, N-ethyl-N-isopropylpropan-2-amine (126 ml, 719mmol) was added through an addition funnel over 12 minutes. The reactionwas stirred in the ice bath for 30 minutes and then at ambienttemperature for 1 hour. The reaction was filtered and the solids washedwith MTBE (about 3 L). The filtrate was concentrated and the residue waspurified by chromatography (3 kg silica, 7:1 to 3:1 Hexane/EtOAc) toafford an oil that slowly solidified under vacuum. The solids wereground using a mortar and pestle, washed with hexanes (about 1000 mL)and dried to afford(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (158 g, 531 mmol, 73.8% yield) as a white solid.

Step I: To 75 mL of EtOAc was added sodium isothiocyanate (0.579 g, 7.15mmol), pyridine (0.874 ml, 10.7 mmol) and(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (2.13 g, 7.15 mmol) and the reaction was heated to 50° C. for30 minutes. The reaction mixture was added to3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (1.12g, 3.57 mmol) and the reaction was stirred for 65 hours at 75° C. Thereaction was cooled and diluted with 50 ml EtOAc and 75 ml 1N NaOH. Theaqueous layer was extracted with EtOAc. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified over silicagel (75% EtOAc/Hexanes) to afford(S)-N-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(1.24 g, 2.31 mmol, 64.5% yield) as a tan solid.

Step J: To a mixture of(S)-N-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(1.24 g, 2.31 mmol) in EtOH (25 ml) and H₂O (1.09 ml, 2.31 mmol) wasadded concentrate HCl (0.480 ml, 5.77 mmol) and the reaction was heatedat reflux for 8 hours. The reaction was allowed to cool to ambienttemperature and stirred overnight. The mixture was concentrated to aresidue that was dissolved in EtOAc and saturated aqueous NaHCO₃. Thecombined organic layers were washed with water, dried over Na₂SO₄,filtered and concentrated. The residue was purified over silica gel (3%MeOH/CH₂Cl₂) to afford(S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolas cream solids. The solids were dissolved in CH₂Cl₂ (25 ml) and 1N HClin Et₂O (20 ml) was added. The mixture was concentrated to dryness anddried in the vacuum oven to afford(S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride (0.569 g, 49.9% yield) as an off-white solid. Massspectrum (apci) m/z=458.1 (M+H—HCl).

Example 140(S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-2-methylpropane-1,2-diol

Step A: In 1 L glass beaker, ethylhydrazine oxalate (51.4 g, 342 mmol)was combined with water (300 ml). To the resulting slurry, 50% w/v NaOHsolution was added (75.5 g) to adjust the pH to 9.5 (by pH-meter). Themixture was heated to p40° C. and methyl trans-3-methoxyacrylate (24.5ml, 228 mmol) was added dropwise over 1 hours. The pH was adjustedperiodically to about 9.0-9.5 by the addition of a 50% w/v NaOHsolution. After the completion of addition, the mixture was agitated foradditional 3 hours at 40° C. and the pH was adjusted occasionally toabout 9.0-9.5. The mixture was cooled to 5° C. and filtered. Thefiltrate was evaporated to about 150 ml, cooled to 5° C. and filtered.The filtrate was acidified to pH 3-4 with 6M HCl (45 ml) and extracted 8times with a 3:1 mixture of chloroform/isopropanol. The combinedextracts were dried (MgSO₄), filtered and concentrated. The crudeproduct was purified over silica gel (20% MeOH/EtOAc) to afford1-ethyl-1H-pyrazol-5-ol (18.3 g, 71% yield) as a yellow solid.

Step B: 5-Bromo-3-nitropicolinonitrile (24.0 g, 105 mmol),1-ethyl-1H-5-ol (13.0 g, 116 mmol), and sodium carbonate (11.2 g, 105mmol) were combined with acetonitrile (400 ml). The mixture was heatedto reflux for 20 hours. The mixture was then cooled to ambienttemperature, filtered and evaporated. The residue was dissolved in ethylacetate (800 ml) and washed with water (3×200 ml) and brine, dried(MgSO₄), filtered and evaporated. The crude material was purified oversilica gel (15:35:50, then 20:30:50 ethyl acetate/chloroform/hexane) toafford 5-bromo-3-(1-ethyl-1H-pyrazol-5-yloxy)picolinonitrile (16.4 g,53% yield) as a white solid.

Step C: 5-Bromo-3-(1-ethyl-1H-pyrazol-5-yloxy)picolinonitrile (16.1 g,55 mmol) and cesium carbonate (17.9 g, 55 mmol) were combined with DMF(160 ml) and pyridine-2-thiol (6.1 g, 55 mmol) dissolved in DMF (40 ml)was added dropwise over 30 minutes. The mixture was then agitated for 1hour, quenched with saturated ammonium chloride solution and extractedwith ethyl acetate. The combined organic extracts were washed with waterand brine, dried (MgSO₄), filtered and evaporated. The residue waspurified over silica gel (20-35% ethyl acetate/hexanes) to afford3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (16.6g, 93% yield) as a white solid.

Step D: Preparation of3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinamide:3-(1-Ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (16.6g, 51.33 mmol) was cooled to −10° C. and concentrated HCl (120 ml, 1440mmol) cooled to the same temperature was added slowly. The mixture wasagitated in the cooling bath until solids mostly dissolved (30 minutes).The bath was removed and the mixture was agitated for 24 hours. It wasthen cooled to −10° C. and a mixture of ice (150 g) and 50% w/v NaOH(120 ml) was added slowly, keeping the temperature below 20° C., toadjust the pH to 12-13. The mixture was extracted twice withdichloromethane and the combined organic extracts were washed withsodium bicarbonate solution, dried (MgSO₄), filtered and evaporated toafford 3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinamide(16.5 g, 94% yield) as thick amber oil which later solidified.

Step E: A 3 M solution of KOH (15.99 ml, 47.98 mmol) was chilled in a 0°C. bath, bromine (0.5120 ml, 9.996 mmol) was added in one portion andthe mixture was stirred 15 minutes. A solution of3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinamide (1.365g, 3.998 mmol) dissolved in dioxane (10 ml) was added. The resultingmixture was then stirred overnight at ambient temperature. The dioxanewas mostly removed in vacuo and the resulting aqueous mixture wasextracted with EtOAc and the organics washed with water, dried overNa₂SO₄, filtered and concentrated to afford crude3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ythio)pyridin-2-amine (1.12g, 3.574 mmol, 89.39% yield) (82% product and 18% starting material byLC.) The crude product was carried directly into next reaction withoutfurther purification.

Step F: (R)-2,2,5,5-Tetramethyl-1,3-dioxolane-4-carbaldehyde (16 g, 101mmol) (Burger, A. Synthesis 1989, (2) 93-97) was dissolved in 1:1methanol:water (250 mL), and hydroxylamine hydrochloride (7.0 g, 101mmol) and Na₂CO₃ (5.4 g, 51 mmol) were added and the reaction wasstirred at ambient temperature for 2 hours. The methanol was partiallyremoved in vacuo and the aqueous layer was extracted with CH₂Cl₂, dried,filtered, and concentrated to afford(S)-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbaldehyde oxime (13 g, 75mmol, 74% yield) as an amber oil.

Step G: (S)-2,2,5,5-Tetramethyl-1,3-dioxolane-4-carbaldehyde oxime (13g, 75.1 mmol) was dissolved in DMF (200 mL) and cooled in an ice bath.1-Chloropyrrolidine-2,5-dione (10.0 g, 75.1 mmol) was added and thereaction was stirred overnight while slowly warming to ambienttemperature. The pale yellow solution was poured into water (1.5 L) andextracted with EtOAc. The organic layers were washed with water andbrine, dried, filtered and concentrated. The residue was purified oversilica gel (40% EtOAc in hexanes) to afford(R)-N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoyl chloride(12.4 g, 59.7 mmol, 79.6% yield).

Step H: (R)-N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoylchloride (12.4 g, 59.7 mmol) was dissolved in Et₂O (200 mL) and cooledin an ice bath. Methanesulfonyl chloride (4.6 ml, 59.7 mmol) was added.Triethylamine (8.3 ml, 59.7 mmol) was added slowly and the reaction wasstirred in an ice bath for 30 minutes. The reaction was filtered andconcentrated. The residue was purified over silica gel (100% CH₂Cl₂) toafford(R)-2,2,5,5-tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoylchloride (11.3 g, 39.55 mmol, 66.22% yield) as a white solid.

Step I: To 30 mL of EtOAc was added sodium isothiocyanate (0.0970 g,1.20 mmol), pyridine (0.195 ml, 2.39 mmol) and(R)-2,2,5,5-tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoylchloride (0.342 g, 1.20 mmol). The reaction was heated to 60° C. Thereaction was cooled and diluted with 50 ml EtOAc and 50 ml 1N NaOH. Theaqueous layer was extracted with EtOAc. The combined organic layers weredried over Na₂SO₄, filtered and concentrated in-vacuo. The residue waspurified over silica gel (50% EtOAc/Hexanes) to afford(S)-N-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine(0.134 g, 0.255 mmol, 32.0% yield).

Step J: To a mixture of(S)-N-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine(0.134 g, 0.255 mmol) in EtOH (5 ml) and water (0.227 ml, 0.255 mmol)was added concentrated HCl (0.0531 ml, 0.637 mmol) and the reactionheated at reflux for 5 hours. The reaction was concentrated to a residuethat was partitioned between EtOAc and saturated aqueous NaHCO₃solution. The combined organic layers were dried over Na₂SO₄, filteredand concentrated to give(S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-2-methylpropane-1,2-diol(0.115 g, 92.9% yield) as a white solid. Mass Spectrum (apci) m/z=468.1(M+H—H₂O).

Example 141(S)-1-(5-(5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride

Step A: Thiourea (22.1 g, 291 mmol) was added to a solution of2-bromo-3-methylpyridine (25.0 g, 145 mmol) in ethanol (500 mL) andrefluxed overnight. The reaction was cooled to ambient temperature, anda 25% aqueous solution of sodium hydroxide (2.33 ml, 14.5 mmol) wasadded. The reaction was heated at reflux for an hour and cooled. A waxysolid formed. The reaction mixture was partitioned between ethyl acetate(600 mL) and water (1 L), and the aqueous layer was extracted with ethylacetate. The combined organic layers were washed with brine, dried, andconcentrated. The solids were triturated with ether (150 mL) for an hourand filtered to afford 3-methylpyridine-2-thiol (5.69 g, 45.5 mmol,31.3% yield) as a yellow powder.

Step B: To a solution of 2-methylpyridin-3-ol (11.8 g, 108 mmol) in DMFat 0° C. was added sodium hydride (60% dispersion in oil, 4.32 g, 108mmol) in small portions and the reaction was warmed to ambienttemperature. To this mixture was added 5-bromo-3-nitropicolinonitrile(24.6 g, 108 mmol) and the reaction was stirred overnight at ambienttemperature. The reaction was poured into water (1000 mL) and theaqueous layer extracted with EtOAc. The combined organic layers werewashed with water and brine, dried over MgSO₄ and concentrated in vacuoto yield 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g, 48%).

Step C: 3-Methylpyridine-2(1H)-thione (0.906 g, 7.24 mmol) and5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (2.00 g, 6.89 mmol)were dissolved in DMF (12 mL) and the mixture was cooled to 0° C. Sodiumhydride (95%; 0.183 g, 7.24 mmol) was slowly added and the reaction waswarmed to ambient temperature and stirred overnight. The reactionmixture was poured into water (100 mL), stirred for 30 minutes, thenfiltered to afford a solid which was purified over silica gel (2:3hexanes:ethyl acetate). Concentration of the second UV active fractionto elute afforded5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)picolinonitrile(1.40 g, 4.19 mmol, 60.7% yield) as a pale yellow/off whitepowder/crystals.

Step D: Concentrated sulfuric acid (8 mL) was added to5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)picolinonitrile(1.40 g, 4.19 mmol). The reaction was stirred over the weekend, thenpoured onto ice (100 g), cooled in an ice bath and made basic to pH 10with 50% NaOH. The reaction mixture was extracted with ethyl acetate,washed with brine, dried (MgSO₄), and concentrated to afford5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)picolinamide(1.40 g, 3.97 mmol, 94.9% yield) as a colorless oil which became a whitecrystalline solid overnight under vacuo.

Step E: To a solution of 2N sodium hydroxide (8.94 ml, 17.9 mmol) at 0°C. was added bromine (0.825 g, 5.16 mmol) in one portion. The reactionwas stirred for 15 minutes and a solution of5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)picolinamide(1.40 g, 3.97 mmol) in dioxane (30 mL) was added. The reaction wasstirred at ambient temperature for one hour, and then at 80° C. for anadditional hour. The reaction was cooled, then stirred overnight atambient temperature. Concentrated HCl was added to adjust the reactionmixture to about pH 2, and the mixture was stirred about 20 minutesuntil carbon dioxide formation stopped. The mixture was partitionedbetween 2N NaOH and ethyl acetate. The organic layer was washed withwater and brine, dried, and concentrated. The residue was trituratedwith 1:5 dichloromethane (60 mL), filtered, washed with hexanes, anddried to afford5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-amine(0.920 g, 2.84 mmol, 71.4% yield) as a light yellow powder.

Step F: To 1000 mL of DI water was added hydroxyl amine hydrochloride(51.0 g, 734 mmol) and the mixture was stirred for 5 minutes. Sodiumcarbonate (38.1 g, 360 mmol) was added in 3 large portions and thereaction was stirred for 15 minutes. THF (700 mL) was added to thereaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734mmol) in 800 mL of THF was added in 1 portion. The reaction was stirredfor 4 hours and poured into a 4 L separatory funnel and the layers wereseparated. The aqueous layer was extracted twice with MTBE (about 3000mL total). The combined organic layers were washed with water (700 mL)and brine (300 mL), dried over MgSO₄, and concentrated in vacuo toafford (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%)as a clear viscous oil.

Step G: To a 4-neck 2 L round bottom flask was added(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135.1 g, 729.4 mmol)dissolved in 750 mL of DMF. The reaction was placed in a water bath and1-chloropyridine-2,5-dione (97.40 g, 729.4 mmol) was added in portionsover 2 minutes. The reaction was stirred in a water bath for 3 hours,then diluted with 2 L of MTBE and washed with 1 L of water. The waterwas extracted with 500 mL of MTBE. The combined organic layers werewashed with water (5×800 mL) and brine (300 mL), dried over MgSO₄ andconcentrated in vacuo to afford added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,98%) as a green viscous oil.

Step H: To a 4 neck 5 L flask was added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,719 mmol) in 2.5 L of THF. The material was cooled to 3° C. andmethanesulfonyl chloride (56.1 ml, 719 mmol) as added in 10 mL portionsover 10 minutes. N-ethyl-N-isopropylpropan-2-amine (126 ml, 719 mmol)was added through an addition funnel over 12 minutes. The reaction wasstirred in the ice bath for 30 minutes and then at ambient temperaturefor 1 hour. The reaction was filtered and the solids were washed withMTBE (about 3 L). The filtrate was concentrated and the residue waspurified over silica gel (7:1 to 3:1 Hexanes/EtOAc) to afford an oilthat slowly solidified under vacuum. The solids were ground using amortar and pestle, washed with hexanes (about 1000 mL) and dried toafford (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (158 g, 531 mmol, 73.8% yield) as a white solid.

Step I: To acetonitrile (50 mL) was added sodium isothiocyanate (0.1749g, 2.158 mmol), pyridine (0.3740 ml, 4.624 mmol), followed by(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (0.5507 g, 1.850 mmol), and the resulting mixture was heated to60° C. for 30 minutes.5-(3-Methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-amine(0.500 g, 1.541 mmol) was added and the reaction was stirred overnightat 60° C. The reaction was concentrated in vacuo and the residue waspartitioned between ethyl acetate and 1N NaOH. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried (MgSO₄) andconcentrated. The residue was dried over silica gel (100% ethylacetate). Concentration of the major UV active fraction with an Rf of0.5 afforded(S)-N-(5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.565 g, 1.030 mmol, 66.8% yield) as an off white powder/crystals.

Step J: To a solution of(S)-N-(5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.565 g, 1.03 mmol) in ethanol (25 mL) was added an aqueous solution of6N HCl (2 mL). The reaction was heated at 80° C. for 2 hours, cooled toambient temperature, stirred for 30 minutes, then cooled at 0° C. for anhour. The reaction was filtered, washed with cold ethanol, hexanes, anddried to afford(S)-1-(5-(5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride (0.450 g, 0.891 mmol, 86.5% yield) as white crystals. MassSpectrum (apci) m/z=469.1 (M+H—HCl).

Example 142(S)-1-(5-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride

Step A: A flask was charged with 2,4-dimethylpyridin-3-ol (9.0 g, 73.1mmol) and DMF (80 mL) was added. Sodium hydride (2.03 g, 80.4 mmol) wasadded and the reaction was stirred for 15 minutes.5-Bromo-3-nitropicolinonitrile (16.7 g, 73.1 mmol) was added and thereaction was stirred for 25 minutes. The reaction mixture was pouredinto 600 mL saturated NH₄Cl and 600 mL water and then filtered, washedwith water and a small amount of hexanes, and dried over high vacuum toprovide 5-bromo-3-(2,4-dimethylpyridin-3-yloxy)picolinonitrile (20.5 g,67.4 mmol, 92.2% yield) as a light tan solid.

Step B: Pyridin-2(1H)-thione (0.768 g, 6.90 mmol) and5-bromo-3-(2,4-dimethylpyridin-3-yloxy)picolinonitrile (2.00 g, 6.58mmol) were added to DMF (12 mL) and cooled to 0° C. 95% Sodium hydride(0.174 g, 6.90 mmol) was slowly added and the reaction was warmed toambient temperature and stirred overnight. The reaction mixture waspoured into water (100 mL) and stirred for 30 minutes. A cloudy milkysolution that was not filterable resulted. The reaction was extractedtwice with ethyl acetate. The combined organic layers were washed twicewith water and brine, dried, and concentrated. The residue was purifiedover silica gel (2:3 to 0:1 hexane:ethyl acetate) to afford3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile(2.03 g, 6.07 mmol, 92.3% yield) as a white powder.

Step C: Concentrated sulfuric acid (8 mL) was added to3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile(2.03 g, 6.07 mmol). The reaction was stirred overnight, then pouredonto ice (100 g), cooled in an ice batch and made basic to pH 10 with50% NaOH. The reaction was extracted with ethyl acetate, washed withbrine, dried (MgSO₄), and concentrated to afford3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinoamide (2.02g, 5.73 mmol, 94.4% yield) as a white solid.

Step D: To a solution of 2N sodium hydroxide (12.9 ml, 25.8 mmol) at 0°C. was added bromine (1.19 g, 7.45 mmol) in one portion. The reactionwas stirred 15 minutes, then a solution of3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (2.02g, 5.73 mmol) in dioxane (30 mL) was added. The reaction was stirred atambient temperature for one hour, at 80° C. for an additional hour, thenovernight at ambient temperature. Concentrated hydrochloric was added toadjust the mixture to about pH 2. The reaction was stirred for 20minutes until CO₂ formation subsided and the reaction was homogenous.The reaction was partitioned between 2N NaOH and ethyl acetate. Theorganic layer was washed with water and brine, dried, and concentratedto afford3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine(1.90 g, 4.92 mmol, 85.8% yield).

Step E: In 1000 mL of DI water was added hydroxyl amine hydrochloride(51.0 g, 734 mmol) and the reaction was stirred for 5 minutes. Sodiumcarbonate (38.1 g, 360 mmol) was added in 3 large portions and thereaction was stirred for 15 minutes. THF (700 mL) was added to thereaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734mmol) was added in 1 portion in 800 mL of THF. The reaction was stirredfor 4 hours and poured into a 4 L separatory funnel and the layersseparated. The aqueous layer was extracted twice with MTBE (about 3000mL total). The combined organic layers were washed with water (700 mL)and brine (300 mL), dried over MgSO₄, and concentrated in vacuo toafford (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%)as a clear viscous oil.

Step F: to a 4-neck 2 L round bottom flask was added(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135.1 g, 729.4 mmol)and 750 mL of DMF. The reaction was placed in a water bath and1-chloropyrrolidine-2,5-dione (97.40 g, 729.4 mmol) as added in portionsover 2 minutes. The reaction was stirred in the water bath for 3 hours,then diluted with 2 L of MTBE and washed with 1 L of water. The waterwas extracted with 500 mL of MTBE. The combined organic layers werewashed with water (5×800 mL) and brine (300 mL), dried over MgSO₄ andconcentrated in vacuo to afford added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,98%) as a green viscous oil.

Step G: To a 4 neck 5 L flask was added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,719 mmol) in 2.5 L of THF. The material was cooled to 3° C. andmethanesulfonyl chloride (56.1 ml, 719 mmol) was added in 10 mL portionsover 10 minutes. N-ethyl-N-isopropylpropan-2-amine (126 ml, 719 mmol)was added through an addition funnel over 12 minutes. The reaction wasstirred in the ice bath for 30 minutes and then at ambient temperaturefor 1 hour. The reaction was filtered and the solids were washed withMTBE (about 3 L). The filtrate was concentrated and the residue waspurified over silica gel (7:1 to 3:1 Hexanes/EtOAc) to afford an oilthat slowly solidified under vacuum. The solids were ground using amortar and pestle, washed with hexanes (about 1000 mL) and dried toafford (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (158 g, 531 mmol, 73.8% yield) as a white solid.

Step H: To acetonitrile (50 mL) was added sodium isothiocyanate (0.1469g, 1.813 mmol), pyridine (0.3141 ml, 3.884 mmol), followed by(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (0.4626 g, 1.554 mmol) and the resulting mixture was heated to60° C. for 30 minutes.3-(2,4-Dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine(0.500 g, 1.295 mmol) was added and the reaction was stirred overnightat 60° C. The reaction was concentrated in vacuo and the residue waspartitioned between ethyl acetate and 1N NaOH. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried (MgSO₄) andconcentrated. The residue was purified over silica gel (100% ethylacetate). Concentration of the major UV component with an Rf of 0.5afforded(S)-N-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.360 g, 0.6561 mmol, 50.7% yield) as a light yellow powder.

Step I: To a solution of(S)-N-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.360 g, 0.656 mmol) in ethanol (25 mL) was added an aqueous 6Nsolution of HCl (2 mL). The reaction was heated at 80° C. for 2 hours,then cooled to ambient temperature, stirred for 30 minutes, then cooledto 0° C. Ether (25 mL) was slowly added to initiateprecipitation/crystallization. The reaction was stirred 30 minutes, thenfiltered. The solids were washed with ether several times, then hexanes,and dried overnight under vacuum at 50° C. to afford(S)-1-(5-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride (0.205 g, 0.406 mmol, 61.9% yield) as a light yellowpowder/fine crystals. Mass Spectrum (apci) m/z=469.2 (M+H—HCl).

Example 143(S)-2-methyl-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diolhydrochloride

Step A: To 600 mL of DMF in a 4 neck 3000 mL round bottom flask equippedwith an overhead stir mechanism under nitrogen was added2-methylpyridin-3-ol (71.8 g, 658 mmol), and the reaction was cooled to2° C. 60% sodium hydride (26.3 g, 658 mmol) was added over 30 minuteswhile maintaining the internal temperature below 10° C. The reaction wasstirred while warming to ambient temperature for 1 hour. To the reactionwas added 5-bromo-3-nitropicolinonitrile (150 g, 658 mmol) in a solutionof 400 mL of DMF in two portions and the reaction held at ambienttemperature for 1.5 hours. Pyridine-2-thiol (73.1 g, 658 mmol) was addedas a solid in portions at ambient temperature and the reaction wasstirred for 15 minutes to dissolve the material. The reaction was cooledto 3° C. and sodium hydride (26.3 g, 658 mmol) again was added inportions over about 35 minutes while maintaining the reactiontemperature below 10° C. The reaction was removed from the ice bath andwarmed to ambient temperature while stirring for 12 hours. The reactionwas diluted with 4 volumes (8 L) of brine and stirred for 30 minutes, atwhich point solid formed. The solid was removed by filtration and thefiltrate was extracted with MTBE (10 L total). The MTBE phase wasconcentrated in vacuo. The solid was combined with concentrated materialand dissolved in ethyl acetate (3 L). The EtOAc was washed with brine,dried over MgSO₄, filtered and concentrated in vacuo. The solid thatformed was ground into a powder and dried in vacuo for 4 hours. Thematerial was taken up in 30 mL of MTBE/10 g of product and the reactionwas stirred for 30 minutes. The solid was filtered and dried in vacuo (2hours). The mother liquor was concentrated and triturated again withMTBE (same dilution rate). The solids were combined and dried for 3hours in vacuo to yield3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (181 g,85%)

Step B: To concentrated H₂SO₄ (90 mL) cooled with an ice bath was added3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (43 g,130 mmol) in portions such that the internal temperature did not exceed50° C. but did not go below 25° C. After complete addition, the mixturewas stirred in the ice bath until the reaction started to cool, at whichpoint the reaction was removed from the ice bath and the mixture washeated to 50° C. The reaction was cooled to ambient temperature andslowly added to ice water over 3 minutes (about 1400 mL of 30% ice inwater). The mixture was further cooled in an ice bath to 5° C. Themixture was neutralized to pH ˜10 with 4M NaOH (about 800 mL) such thatthe internal temperature did not exceed 20° C., at which point a solidformed. The mixture was stirred for 20 minutes, then filtered and washedwith MTBE (5×150 mL), hexanes (5×100 mL), and dried at under vacuum toafford 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (43g, 96%).

Step C: To a 3-neck 2 L round bottom flask was added 2M aqueous sodiumhydroxide (343 ml, 686 mmol) and the solution was cooled in an ice bath.Bromine (12 ml, 257 mmol) was added the reaction was stirred for 30minutes while the ice bath was removed.3-(2-Methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (58 g, 171mmol) was added as a slurry in about 600 mL of dioxanes in 1 portion.After 30 minutes, concentrated HCl was added in 1 mL portions to aboutpH 1. The reaction was stirred for 15 minutes and 4N NaOH was added tothe solution to about pH 10. The aqueous mixture was extracted withEtOAc (3×750 mL), washed with water (2×250 mL) and brine (300 mL), driedover MgSO₄, filtered and concentrated. The material was dried in vacuoat 50° C. at which point a red solid formed. The solid was trituratedwith CH₂Cl₂ (about 40 mL of CH₂Cl₂ to 5 g of material) and the solidfiltered. The solid was washed with CH₂Cl₂ and dried under vacuum at 50°C. The filtrate was concentrated in vacuo and material purified oversilica gel (3% MeOH/CH₂Cl₂) to afford a red solid. The two crops werecombined to afford3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (24 g,45%).

Step D: (R)-2,2,5,5-Tetramethyl-1,3-dioxolane-4-carbaldehyde (16 g, 101mmol) [Burger, A. Synthesis 1989, (2) 93-97] was dissolved in 1:1methanol:water (250 mL) and hydroxylamine hydrochloride (7.0 g, 101mmol), and Na₂CO₃ (5.4 g, 51 mmol) was added. The reaction was stirredat ambient temperature for 2 hours. The methanol was partially removedin vacuo and the aqueous layer was extracted with CH₂Cl₂, dried,filtered and concentrated to afford(S)-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbaldehyde oxime (13 g, 75mmol, 74% yield) as an amber oil.

Step E: (S)-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbaldehyde oxime (13g, 75.1 mmol) was dissolved in DMF (200 mL) and cooled in an ice bath.1-Chloropyrrolidine-2,5-dione (10.0 g, 75.1 mmol) was added and thereaction was stirred overnight while slowly warming to ambienttemperature. The pale yellow solution was poured into water (1.5 L) andextracted with EtOAc. The organic layers were washed with water andbrine, dried, filtered and concentrated. The residue was purified oversilica gel (40% EtOAc in hexanes) to afford(R)-N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoyl chloride(12.4 g, 59.7 mmol, 79.6% yield).

Step F: (R)-N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoylchloride (12.4 g, 59.7 mmol) was dissolved in Et₂O (200 mL) and cooledin an ice bath. Methanesulfonyl chloride (4.6 ml, 59.7 mmol) was added.Triethylamine (8.3 ml, 59.7 mmol) was added slowly and the reaction wasstirred in an ice bath for 30 minutes. The reaction was filtered andconcentrated. The residue was purified over silica gel (100% CH₂Cl₂) toafford(R)-2,2,5,5-tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoylchloride (11.3 g, 39.55 mmol, 66.22% yield) as a white solid.

Step G:(R)-2,2,5,5-Tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoylchloride (138 mg, 0.483 mmol) was dissolved in CH₃CN (3 mL). NaNCS (39.2mg, 0.483 mmol) and pyridine (104 μL, 1.29 mmol) were added, and thereaction was heated to 45° C. for 45 minutes.3-(2-Methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (100 mg,0.322 mmol) was added, and the reaction was heated to 65° C. overnight.The reaction was partitioned between EtOAc and water, dried, filteredand concentrated. The residue was purified over silica gel (80% EtOAc inhexanes) to afford(S)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine(145 mg, 0.277 mmol, 86.1% yield).

Step H:(S)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine(145 mg, 0.2774 mmol) was dissolved in EtOH (5 mL), and 6M HCl (0.3 mL)was added. The reaction was stirred at ambient temperature for 2 hoursand then at 70° C. for 2 hours. The reaction was cooled to ambienttemperature and partitioned between CH₂Cl₂ and saturated aqueous sodiumbicarbonate. The organic layer was dried, filtered, concentrated andpurified over silica gel (10% methanol in EtOAc) to afford(S)-2-methyl-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diolhydrochloride (111.7 mg, 0.215 mmol, 77.6% yield) as a pale yellow solidafter HCl salt formation. Mass Spectrum (apci) m/z=465.2 (M+H—HCl).

Example 144(S)-1-(5-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride

Step A: To a solution of 2-methylpyridin-3-ol (11.8 g, 108 mmol) in DMFat 0° C. was added sodium hydride (60% dispersion in oil, 4.32 g, 108mmol) in small portions and the reaction was warmed to ambienttemperature. 5-Bromo-3-nitropicolinonitrile (24.6 g, 108 mmol) was addedand the reaction was stirred overnight at ambient temperature. Thereaction was poured into water (1000 mL) and the aqueous layer extractedwith EtOAc. The combined organic layers were washed with water andbrine, dried over MgSO₄ and concentrated in vacuo to yield5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g, 48%).

Step B: To 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g, 52mmol) was added concentrated H₂SO₄ (30 mL) and the slurry was stirredovernight, at which point the material was fully dissolved. The reactionwas poured into 0° C. water in small portions. While maintaining thetemp below 20° C., the aqueous layer was basified by the addition ofNaOH pellets, to a pH of about 5, at which point a solid formed. Thesolid was filtered, and the remaining aqueous layer was extracted withEtOAc. The organic layers, combined with the solid, were washed withbrine, dried over MgSO₄ and concentrated in vacuo to yield5-bromo-3-(2-methylpyridin-3-yloxy)picolinamide (11 g, 69%).

Step C: To a solution of NaOH (2M, 90 mL, 182 mmol) at 0° C. was addedbromine (8.71 g, 54 mmol) and the reaction was stirred at 0° C. for 30minutes. 5-Bromo-3-(2-methylpyridin-3-yloxy)picolinamide (11.2 g, 36.3mmol) in dioxanes (100 mL) was added and the reaction was stirred atambient temperature for 1 hour followed by heating at 80° C. for 1 hour.The reaction was cooled to ambient temperature and acidified to pH 1using concentrated HCl. The reaction was basified and a solidprecipitated. The solid was filtered and dried in vacuo to yield product5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (4.1 g, 41%).

Step D: In 1000 mL of DI water was added hydroxyl amine hydrochloride(51.0 g, 734 mmol) and the reaction was stirred for 5 minutes. Sodiumcarbonate (38.1 g, 360 mmol) was added in 3 large portions and thereaction was stirred for 15 minutes. THF (700 mL) was added to thereaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734mmol) was added in 1 portion in 800 mL of THF. The reaction was stirredfor 4 hours and poured into a 4 L separatory funnel and the layersseparated. The aqueous layer was extracted twice with MTBE (3000 mLtotal). The combined organic layers were washed with water (700 mL) andbrine (300 mL), dried over MgSO₄ and concentrated in vacuo to afford(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%) as aclear viscous oil.

Step E: To a 4-neck 2 L round bottom flask was added(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135.1 g, 729.4 mmol)and dissolved in 750 mL of DMF. The reaction was placed in a water bathand 1-chloropyrrolidine-2,5-dione (97.40 g, 729.4 mmol) was added inportions over 2 minutes. The reaction was stirred in the water bath for3 hours, then diluted with 2 L of MTBE and washed with 1 L of water. Theaqueous layer was extracted with 500 mL of MTBE. The combined organiclayers were washed with water (5×800 mL) and brine (300 mL), dried overMgSO₄ and concentrated in vacuo to afford added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,98%) as a green viscous oil.

Step F: In a 4 neck 5 L flask was added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,719 mmol) in 2.5 L of THF. The material was cooled to 3° C. andmethanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portionsover 10 minutes. N-ethyl-N-iospropylpropan-2-amine (126 ml, 719 mmol)was added through an addition funnel over 12 minutes. The reaction wasstirred in an ice bath for 30 minutes and then at ambient temperaturefor 1 hour. The reaction was filtered and the solids washed with MTBE (3L). The filtrate was concentrated and the residue was purified oversilica gel (3 kg silica, 7:1 to 3:1 Hexane/EtOAc) to afford an oil thatslowly solidified under vacuum. The solids were ground using a mortarand pestle, washed with hexanes (about 1000 mL) and dried to afford(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (158 g, 531 mmol, 73.8% yield) as a white solid.

Step G: In 100 mL of acetonitrile was added sodium thioisocyanate (1.5g, 20 mmol), pyridine (3.5 g, 44 mmol), followed by(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (5.2 g, 18 mmol) and the reaction heated to 60° C. for 30minutes. 5-Bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (4.1 g, 15mmol) was added and the reaction was heated overnight at 60° C. Thereaction was concentrated to one quarter volume and the residue waspartitioned between EtOAc and water made basic with 1N NaOH. Thecombined organic layers were separated and the aqueous layer extractedwith EtOAc. The combined organic layers were washed with brine, driedover MgSO₄ and concentrated in vacuo. The material was purified onsilica gel (25% EtOAc in CH₂Cl₂) to afford(S)-N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(5.4 g, 73%).

Step H: To a solution of(S)-N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(3.1 g, 6.14 mmol) in dioxanes (30 mL) continuously purged with nitrogenwas added Xanphos (0.177 g, 0.303 mmol), Pd₂dba₃ (0.14 g, 0.153 mmol),methyl 3-mercaptopropanoate (0.73 g, 6.14 mmol) andN,N-diisopropylethylamine (1.17 mL, 6.45 mmol) and the reaction washeated overnight at 80° C. The reaction was concentrated in vacuo andthe residue purified over silica gel (5% MeOH/CH₂Cl₂) to afford(S)-methyl3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate(2.3 g, 68%).

Step I: (S)-Methyl3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate(2.0 g, 3.68 mmol) was dissolved in THF (20 mL) and nitrogen was bubbledthrough the solution for 5 minutes. Potassium 2-methylpropan-2-olate (1Min THF, 11.0 ml, 11.0 mmol) was added and the reaction was stirred atambient temperature for 1 minute. 1-Bromo-2-methoxyethane (0.518 ml,5.52 mmol) was added and the reaction was stirred at ambient temperaturefor 20 minutes. The reaction was partitioned between EtOAc and aqueousNH₄Cl, dried, filtered and concentrated. The residue was purified oversilica gel (100% EtOAc) to afford(S)-N-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(1.9 g, 3.68 mmol, 100% yield).

Step J:(S)-N-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(1.9 g, 3.68 mmol) was dissolved in EtOH (50 mL) and 6M HCl (3 mL) addedand heated to 60° C. for 1.5 hours. The reaction was cooled to ambienttemperature and partitioned between CH₂Cl₂ and saturated aqueous sodiumbicarbonate, extracted with CH₂Cl₂, dried, filtered and concentrated.The residue was purified over silica gel (0 to 10% methanol in EtOAc) toafford(S)-1-(5-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride (1.13 g, 2.39 mmol, 65.0% yield) as a white solid afterHCl salt formation. Mass Spectrum (apci) m/z=436.1 (M+H—HCl).

Example 145(1S,2S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-3-methoxypropane-1,2-diolhydrochloride

Step A: 2-Bromopyridin-3-yl acetate (10 g, 46 mmol) was dissolved in THF(80 mL) and triethylamine (32 ml, 231 mmol), ethynyltrimethylsilane(19.5 ml, 139 mmol), and CuI (0.44 g, 2.3 mmol) were added. The mixturewas degassed with argon for 15 minutes. PdCl₂(PPh₃)₂ (1.6 g, 2.3 mmol)was added and the mixture stirred under argon at ambient temperature for18 hours. The reaction was concentrated in vacuo, dissolved in 25% EtOAcin hexanes, filtered and purified over silica gel (25% ethylacetate/hexanes) to afford 2-((trimethylsilyl)ethynyl)pyridin-3-ylacetate (9.7 g, 41 mmol).

Step B: To a solution of 2-((trimethylsilyl)ethynyl)pyridin-3-yl acetate(9.5 g, 41 mmol) in THF (200 mL) was added water (25 ml). The reactionwas cooled to 0° C. and TBAF (1M, 45 ml, 45 mmol) was added. The mixturewarmed to ambient temperature and stirred for 1 hour. Water (100 mL) wasadded and the volume was reduced by half. The product was extracted intoether (3×100 mL), washed with brine and dried over MgSO₄. The solutionwas concentrated in vacuo to afford 2-ethynylpyridin-3-yl acetate (5.5g, 34 mmol) as a light brown oil.

Step C: To a solution of 2-ethynylpyridin-3-yl acetate (5.0 g, 31 mmol)in ethanol (50 mL) was added PtO₂ (0.50 g, 2.2 mmol). The mixture wasdegassed with nitrogen and placed under a double-layer balloon ofhydrogen. The reaction was stirred at ambient temperature for 30minutes. The mixture was filtered and concentrated in vacuo to give2-ethylpyridin-3-yl acetate (5.1 g, 31 mmol) that was used withoutfurther purification.

Step D: To a solution of 2-ethylpyridin-3-yl acetate (5.1 g, 31 mmol) inethanol (50 mL) was added 3M LiOH (50 mL, 150 mmol). The reactionmixture stirred at ambient temperature for 30 minutes. The mixture wasconcentrated to dryness and purified over silica gel (10% MeOH inCH₂Cl₂) to afford 2-ethylpyridin-3-ol (2.5 g, 20 mmol).

Step E: 2-Ethylpyridin-3-ol (27.5 g, 223 mmol) was dissolved in DMF (900mL) and cooled in an ice bath. 60% Sodium hydride (8.93 g, 223 mmol) wasadded portionwise and stirred in an ice bath for 30 minutes.5-Bromo-3-nitropicolinonitrile (50.9 g, 223 mmol) was added in oneportion and the reaction was stirred in an ice bath for 1 hour.Pyridine-2(1H)-thione (24.8 g, 223 mmol) was added, followed by 60%sodium hydride (8.93 g, 223 mmol) and reaction was stirred in an icebath slowly warming to ambient temperature overnight. The reaction wasconcentrated in vacuo to about 300 mL and poured into 3 L water withvigorous stirring. The mixture was extracted with EtOAc, washed withwater and brine, dried over sodium sulfate, filtered and concentrated toafford 3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile(81 g, 242 mmol, 108% yield) as a dark oil.

Step F: 3-(2-Ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile(80 g, 239 mmol) was cooled in an ice/acetone bath. 12M Hydrogenchloride (598 ml, 7177 mmol) was chilled in an ice/acetone bath and thenadded slowly to the oil in the flask. After agitating for 40 minutes allthe starting material dissolved and the bath was removed and the mixturewas stirred at ambient temperature over the weekend. The reaction wascooled in an ice bath and 6N NaOH (1200 mL) was added slowly whilekeeping the temperature below 20° C. to a final pH of about 9. Theaqueous mixture was extracted with CH₂Cl₂, washed with water and brine,dried over sodium sulfate, filtered and concentrated to afford3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (71 g, 201mmol, 84% yield) as a dark green foam.

Step G: 3-(2-Ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (71g, 201 mmol) was dissolved in MeOH (1 L). 1-Bromopyrrolidine-2,5-dione(46.6 g, 262 mmol) was added and the reaction was stirred at ambienttemperature for 5 minutes and then cooled in an ice bath. Sodiumhydroxide (41.9 g, 1048 mmol) dissolved in water (200 mL) was addedslowly and the reaction was stirred at ambient temperature for 1 hour,refluxed for 8 hours and then cooled to ambient temperature overnight.The reaction was diluted with 2.5 L water and 0.5 L NH₄Cl and stirredfor 30 minutes. The precipitate was filtered and dried to afford3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (52.6 g,162 mmol, 80.5% yield) as a tan solid.

Step H: (2R,3R)-diethyl 2,3-dihydroxysuccinate (82.99 ml, 485.0 mmol)was dissolved in Toluene (400 mL) and cyclohexanone (55.29 ml, 533.5mmol) and Amberlyst 15 ion-exchange resin (2.0 g) were added and thereaction refluxed under dean stark trap for 12 hours. The reaction wascooled to ambient temperature, filtered and concentrated. The residuewas distilled at 0.5 mM Hg and the 125-140° C. fraction was collected toafford (2R,3R)-diethyl 1,4-dioxaspiro[4.5]decane-2,3-dicarboxylate (91.3g, 66% yield).

Step I: (2R,3R)-diethyl 1,4-dioxaspiro[4.5]decane-2,3-dicarboxylate(91.3 g, 319 mmol) was dissolved in THF (1.5 L) and cooled in ice bath.2M LAH (120 ml, 239 mmol) was added slowly and the reaction stirred at0° C. Small aliquots were taken and ¹H NMR analyzed for completion ofreaction. Sodium sulfate decahydrate was added slowly, and allowed tostir at ambient temperature for 1 hour. The reaction was filteredthrough celite and concentrated to afford batch 1 (45.3 g). The celitewas stirred in EtOAc for 30 min and filtered again to afford batch 2(9.8 g). The celite was stirred again in CH₂Cl₂/MeOH for 30 min andfiltered again to afford batch 3 (1.6 g). The three batches werecombined to afford (2S,3S)-1,4-dioxaspiro[4.5]decane-2,3-diyldimethanol(56.7 g, 88% yield).

Step J: (2S,3S)-1,4-dioxaspiro[4.5]decane-2,3-diyldimethanol (65 g,321.4 mmol) was dissolved in DMF (500 mL) and cooled in an ice bath. 60%Sodium hydride (15.43 g, 385.7 mmol) was added slowly and the reactionwas stirred for 30 minutes in an ice bath then warmed to ambienttemperature for 2 hours. Iodomethane (20.05 ml, 321.4 mmol) was addedand the reaction was stirred at ambient temperature overnight. Themajority of the DMF was removed on a rotary evaporator, and the residuewas partitioned between aqueous NH₄Cl and EtOAc. The organic layer waswashed with brine, dried over sodium sulfate, filtered and concentrated.The residue was purified over 1 Kg of SiO₂ (20 to 40% EtOAc in hexanes)to afford((2S,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decan-2-yl)methanol (31.3g, 144.7 mmol, 45.03% yield) as an oil.

Step K: A solution of methylsulfinylmethane (20.6 ml, 289 mmol) inCH₂Cl₂ (260 mL) at −60° C., was added dropwise to a 2M solution ofoxalyl dichloride (15.2 ml, 174 mmol) in CH₂Cl₂ (80 mL). The mixture wasstirred for 20 minutes and then a solution of((2S,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decan-2-yl)methanol (31.3g, 145 mmol) in CH₂Cl₂ (80 mL) was added dropwise. The mixture wasstirred for 10 minutes and then triethylamine (101 ml, 724 mmol) wasslowly added. The reaction mixture was warmed to ambient temperature andwater was added. When the mixture became clear, it was extracted withCH₂Cl₂, dried over sodium sulfate, filtered and concentrated to affordcrude (2R,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde(34.3 g, 96.2% yield, 87% pure) which was taken on to next reactionwithout further purification.

Step L: Crude(2R,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (31g, 145 mmol) was dissolved in 1:1 methanol:water (600 mL), andhydroxylamine hydrochloride (10.1 g, 145 mmol) and Na₂CO₃ (7.67 g, 72.3mmol) were added. The reaction was stirred at ambient temperature for 3hours. The methanol was removed under reduced pressure and the remainingmaterial was extracted with CH₂Cl₂, dried over sodium sulfate, filteredand concentrated to afford3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (33.6g, 147 mmol, 101% yield) which was taken forward without purification.

Step M: 3-(Methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime(33.2 g, 145 mmol) was dissolved in DMF (600 mL) and cooled in an icebath. 1-Chloropyrrolidine-2,5-dione (19.3 g, 145 mmol) was added and thereaction allowed to slowly warm to ambient temperature overnight. Mostof the DMF was removed under reduced pressure and the remaining materialwas partitioned between water and EtOAc. The organic layer was washedwith water and brine, dried over sodium sulfate, filtered andconcentrated to afford(2R,3S)-N-hydroxy-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (35.6 g, 135 mmol, 93.2% yield) which was taken forward withoutfurther purification.

Step N:(2R,3S)-N-hydroxy-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (35.6 g, 135.0 mmol) was dissolved in Et₂O (600 mL) and cooledin an ice bath. Methanesulfonyl chloride (10.49 ml, 135.0 mmol) wasadded, followed by dropwise addition of triethylamine (18.82 ml, 135.0mmol). The reaction was stirred for 30 minutes and then filtered andconcentrated. The residue was purified on 1 Kg SiO₂ (1 to 5% EtOAc inCH₂Cl₂) to afford(2R,3S)-3-(methoxymethyl)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (22.6 g, 66.12 mmol, 48.98% yield).

Step O:(2R,3S)-3-(Methoxymethyl)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (2.29 g, 6.70 mmol) was dissolved in EtOAc (40 mL), and NaNCS(0.544 g, 6.70 mmol) and pyridine (1.44 ml, 17.9 mmol) were added andthe reaction was heated to 45° C. for 45 minutes.3-(2-Ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (1.45 g,4.47 mmol) was added and the reaction was heated to 70° C. overnight.(2R,3S)-3-(methoxymethyl)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (1.15 g, 3.3 mmol) was dissolved in EtOAc (20 mL). NaNCS (0.270g, 3.3 mmol) and pyridine (0.7 ml, 9.0 mmol) were added and the reactionwas heated to 45° C. for 45 minutes. This solution was added to theinitial reaction and heated to 70° C. overnight. The reaction was cooledand partitioned between EtOAc and water, dried over sodium sulfate,filtered and concentrated. The residue was purified over silica gel (80%EtOAc in Hexane) to affordN-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-((2S,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(1.6 g, 2.70 mmol, 60.4% yield).

Step P:N-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-((2S,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(1.6 g, 2.70 mmol) was dissolved in EtOH (30 mL) and 4N HCl (1 mL) addedand heated to 50° C. overnight. Additional 4N HCl was added (1 mL) andheated for 4 hours. The reaction was cooled to ambient temperature,partitioned between CH₂Cl₂ and saturated aqueous sodium bicarbonate,extracted with CH₂Cl₂, dried over sodium sulfate, filtered andconcentrated. The residue was purified over silica gel (10% methanol inEtOAc) to afford(1S,2S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-3-methoxypropane-1,2-diolhydrochloride (0.957 g, 1.74 mmol, 64.6% yield) as a tan solid after HClsalt formation. Mass Spectrum (apci) m/z=513.1 (M+H—HCl).

Example 146(S)-2-methyl-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diolhydrochloride

Step A: A flask was charged with powdered potassium hydroxide (21.89 g,390.2 mmol), benzoic acid (47.65 g, 390.2 mmol), and DMF (500 mL) wasadded. The mixture was heated at 50° C. for 1 hour.3-Chloropentane-2,4-dione (52.5 g, 390.2 mmol) was added and thereaction was stirred at 50° C. overnight. The reaction was cooled toambient temperature, diluted in water (1.5 L) and extracted with ether(3×500 mL). The combined organic layers were washed with water,saturated NH₄Cl and brine. The organic layer was dried over sodiumsulfate and concentrated in vacuo to afford 2,4-dioxopentan-3-ylbenzoate (82.59 g, 96.12% yield) as a yellow oil.

Step B: A flask was charged with 2,4-dioxopentan-3-yl benzoate (82.59 g,375.0 mmol) and ethanol (1.5 L) was added. Methylhydrazine (39.90 ml,750.1 mmol) in ethanol (150 mL) was added, and the reaction was stirredat ambient temperature for 2 hours, then concentrated in vacuo to afford1,3,5-trimethyl-1H-pyrazol-4-yl benzoate (80 g, 92.6% yield).

Step C: A flask was charged with 1,3,5-trimethyl-1H-pyrazol-4-ylbenzoate (80 g, 347 mmol), and added 500 mL ethanol. 3M NaOH (174 ml,521 mmol) was added and the reaction was stirred at ambient temperaturefor 2 hours. The ethanol was removed in vacuo and the aqueous layer wasextracted with dichloromethane, ethyl acetate anddichloromethane:isopropyl alcohol (4:1). The combined organic layerswere dried over sodium sulfate, filtered and concentrated in vacuo toafford 1,3,5-trimethyl-1H-pyrazol-4-ol (34 g, 78% yield) as white solid.

Step D: A flask was charged with 1,3,5-trimethyl-1H-pyrazol-4-ol (10.46g, 82.89 mmol), and DMF:dioxane (9:1) (700 mL). The reaction mixture wascooled to 0° C. and 60% sodium hydride (3.315 g, 82.89 mmol) was addedportionwise. The reaction mixture was added. The reaction was stirred atambient temperature for 3 hours, then poured slowly into 600 mL waterand stirred for 10 minutes. The resultant solids were filtered and driedto afford 5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile(23.70 g, 97.74% yield) as very lightly tan (white) solid.

Step E: A flask was charged with5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (27.77 g,90.41 mmol), pyridine-2-thiol (10.55 g, 94.93 mmol), and DMF (300 mL).The reaction was cooled to 0° C. and 95% sodium hydride (2.741 g, 108.5mmol) was added portionwise. The reaction was stirred at ambienttemperature overnight, then carefully diluted with water (2 L) andextracted with ethyl acetate. The organic layer was washed with brine(4×500 mL), dried over sodium sulfate and concentrated to afford5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile(29.50 g, 87.43 mmol, 96.70% yield) as yellow solid.

Step F: A flask was charged with5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile(35.19 g, 88.1 mmol), and sulfuric acid (227.3 g, 2317 mmol) and stirredat ambient temperature overnight. Water (100 mL) was added very slowlyto the reaction which was cooled in an ice bath, and then 150 g of icewas added. NaOH (40%) was slowly added until pH was adjusted to about12. The mixture was extracted ethyl acetate (750 mL×2), anddichloromethane (500 mL). The combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo to afford5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinamide(27.69 g, 77.9 mmol, 89% yield).

Step G: A flask was charged with potassium hydroxide (78.8 ml, 236mmol), bromine (4.04 ml, 78.8 mmol) was added and the reaction wasstirred at ambient temperature for 15 minutes.5-(Pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinamide(14 g, 39.4 mmol) in dioxane (280 mL) was added and the reaction wasstirred at ambient temperature overnight. Water (300 mL) was added andthe reaction was extracted with ethyl acetate. The organic layer wasdried over sodium sulfate, filtered and concentrated. The residue waspurified over silica gel (50 to 100% ethyl acetate in hexanes) to afford5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-amine(4.64 g, 14.18 mmol, 36% yield) as yellow solid.

Step H: (R)-2,2,5,5-Tetramethyl-1,3-dioxolane-4-carbaldehyde (16 g, 101mmol) [Burger, A. Synthesis 1989, (2) 93-97] was dissolved in 1:1methanol:water (250 mL). Hydroxylamine hydrochloride (7.0 g, 101 mmol)and Na₂CO₃ (5.4 g, 51 mmol) were added and the reaction was stirred atambient temperature for 2 hours. The methanol was partially removed invacuo and the aqueous layer was extracted with CH₂Cl₂ dried, filteredand concentrated to afford(S)-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbaldehyde oxime (13 g, 75mmol, 74% yield) as an amber oil.

Step I: (S)-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbaldehyde oxime (13g, 75.1 mmol) was dissolved in DMF (200 mL) and cooled in an ice bath.1-Chloropyrrolidine-2,5-dione (10.0 g, 75.1 mmol) was added and thereaction was stirred overnight, slowly warming to ambient temperature.The pale yellow solution was poured into water (1.5 L) and extractedwith EtOAc. The combined organic layers were washed with water andbrine, dried, filtered and concentrated. The residue was purified oversilica gel (40% EtOAc in hexanes) to afford(R)-N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoyl chloride(12.4 g, 59.7 mmol, 79.6% yield).

Step J: (R)-N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoylchloride (12.4 g, 59.7 mmol) was dissolved in Et₂O (200 mL) and cooledin an ice bath. Methanesulfonyl chloride (4.6 ml, 59.7 mmol) was added.Triethylamine (8.3 ml, 59.7 mmol) was added slowly and the reaction wasstirred in an ice bath for 30 minutes. The reaction was filtered andconcentrate. The residue was purified over silica gel (100% CH₂Cl₂) toafford(R)-2,2,5,5-tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoylchloride (11.3 g, 39.55 mmol, 66.22% yield) as a white solid.

Step K: A flask was charged with(R)-2,2,5,5-tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoylchloride (0.371 g, 1.30 mmol), sodium thiocyanate (0.0929 g, 1.15 mmol),pyridine (0.278 g, 0.764 mmol) was added and the reaction was heated to40° C. for 30 minutes.5-(Pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-amine(0.250 g, 0.764 mmol) was added and the reaction was stirred at 70° C.overnight. Water was added and the reaction was extracted with ethylacetate. The organic layer was dried over sodium sulfate, filtered andconcentrated. The residue was purified over silica gel (50 to 100% ethylacetate in hexanes) to afford(S)-N-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine(0.233 g, 56.5% yield) as yellow solid.

Step L: A flask was charged with(S)-N-(5-pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine(0.233 g, 0.432 mmol), ethanol (10 mL), and 3M HCl (0.288 ml, 0.863mmol). The reaction was heated to 75° C. for 1 hour and thenconcentrated in vacuo. Ether was added to the residue and the mixturewas stirred for 2 minutes to precipitate the product. The mixture wasdecanted and the resulting solids were dried in vacuo to afford(S)-2-methyl-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diolhydrochloride (0.248 g, 0.387 mmol, 89.6% yield) as yellow solid. MassSpectrum (apci) m/z=500.1 (M+H—HCl).

Example 147(S)-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride

Step A: A flask was charged with powdered potassium hydroxide (21.89 g,390.2 mmol), benzoic acid (47.65 g, 390.2 mmol), and DMF (500 mL). Themixture was heated at 50° C. for 1 hour. 3-Chloropentane-2,4-dione (52.5g, 390.2 mmol) was added and the reaction was stirred at 50° C.overnight. The reaction was cooled to ambient temperature, diluted inwater (1.5 L) and extracted with ether (3×500 mL). The combined organiclayers were washed with water, saturated NH₄Cl and brine. The organiclayer was dried over sodium sulfate and concentrated in vacuo to afford2,4-dioxopentan-3-yl benzoate (82.59 g, 96.12% yield) as yellow oil.

Step B: A flask was charged with 2,4-dioxopentan-3-yl benzoate (82.59 g,375.0 mmol) and ethanol (1.5 L) was added. To this solution was addedmethylhydrazine (39.90 ml, 750.1 mmol) in ethanol (150 mL). The reactionwas stirred at ambient temperature for 2 hours and concentrated in vacuoto afford 1,3,5-trimethyl-1H-pyrazol-4-yl benzoate (80 g, 92.6% yield).

Step C: A flask was charged with 1,3,5-trimethyl-1H-pyrazol-4-ylbenzoate (80 g, 347 mmol), and 500 mL ethanol was added. 3M NaOH (174ml, 521 mmol) was added and the reaction was stirred at ambienttemperature for 2 hours. The ethanol was removed in vacuo and theaqueous layer was extracted with dichloromethane, ethyl acetate anddichloromethane:isopropyl alcohol (4:1). The combined organic layerswere dried over sodium sulfate, filtered and concentrated in vacuo toafford 1,3,5-trimethyl-1H-pyrazol-4-ol (34 g, 78% yield) as white solid.

Step D: A flask was charged with 1,3,5-trimethyl-1H-pyrazol-4-ol (10.46g, 82.89 mmol), and added DMF:dioxane (9:1) (700 mL). The reactionmixture was cooled to 0° C. and 60% sodium hydride (3.315 g, 82.89 mmol)was added portionwise and the reaction was stirred for 15 minutes.5-Bromo-3-nitropicolinonitrile (18 g, 78.95 mmol) was added and thereaction was stirred at ambient temperature for 3 hours. The reactionwas poured slowly into 600 mL water and stirred for 10 minutes. Theresultant solids were filtered and dried to afford5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (23.70 g,97.74% yield) as very lightly tan (white) solid.

Step E: A flask was charged with5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (27.77 g,90.41 mmol), pyridine-2-thiol (10.55 g, 94.93 mmol), and DMF (300 mL).The reaction was cooled to 0° C. and 95% sodium hydride (2.741 g, 108.5mmol) was added portionwise. The reaction was stirred at ambienttemperature overnight, then carefully diluted with water (2 L) andextracted with ethyl acetate. The organic layer was washed with brine(4×500 mL), dried over sodium sulfate and concentrated to afford5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile(29.50 g, 87.43 mmol, 96.70% yield) as yellow solid.

Step F: A flask was charged with5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile(35.19 g, 88.1 mmol), and sulfuric acid (227.3 g, 2317 mmol) and stirredat ambient temperature overnight. Water (100 mL) was slowly added to thereaction which was cooled in an ice bath, then ice (150 g) was added.40% NaOH was slowly added until the pH was about 12. The mixture wasextracted ethyl acetate (750 mL×2), and dichloromethane (500 mL). Theorganic layers were dried over sodium sulfate and concentrated in vacuoto afford5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinamide(27.69 g, 77.9 mmol, 89% yield).

Step G: A flask was charged with potassium hydroxide (78.8 ml, 236mmol), and bromine (4.04 ml, 78.8 mmol), and the mixture was stirred atambient temperature for 15 minutes.5-(Pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinamide(14 g, 39.4 mmol) in dioxane (280 mL) was added and the reaction wasstirred at ambient temperature overnight. Water (300 mL) was added andthe mixture was extracted with ethyl acetate. The organic layer wasdried over sodium sulfate, filtered and concentrated. The residue waspurified over silica gel (50 to 100% ethyl acetate in hexanes) to afford5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-amine(4.64 g, 14.18 mmol, 36% yield) as yellow solid.

Step H: To 1000 mL of DI water was added hydroxyl amine hydrochloride(51.0 g, 734 mmol) and the reaction was stirred for 5 minutes. Sodiumcarbonate (38.1 g, 360 mmol) was added in 3 large portions and thereaction was stirred for 15 minutes. THF (700 mL) was added, followed by(R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734 mmol) in 800 mLof THF. The reaction was stirred for 4 hours, then poured into a 4 Lseparatory funnel. The layers were separated and the aqueous layer wasextracted twice with MTBE (about 3000 mL total). The combined organiclayers were washed with water (700 mL) and brine (300 mL), dried overMgSO₄ and concentrated in vacuo to afford(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%) as aclear viscous oil.

Step I: To a 4-neck 2 L round bottom flask was added(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135.1 g, 729.4 mmol)and dissolved in 750 mL of DMF. The reaction was placed in a water bathand 1-chloropyrrolidine-2,5-dione (97.40 g, 729.4 mmol) was added inportions over 2 minutes. The reaction was stirred in the water bath for3 hours. The reaction was diluted with 2 L of MTBE and washed with 1 Lof water. The water was extracted with 500 mL of MTBE. The combinedorganic layers were washed with water (5×800 mL) and brine (300 mL),dried over MgSO₄ and concentrated in vacuo to afford added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,98%) as a green viscous oil.

Step J: to a 4 neck 5 L flask was added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,719 mmol) in 2.5 L of THF. The mixture was cooled to 3° C., andmethanesulfonyl chloride (56.1 ml, 719 mmol) was added in 10 mL portionsover 10 minutes. N-ethyl-N-isopropylpropan-2-amine (126 ml, 719 mmol)was added through an addition funnel over 12 minutes. The reaction wasstirred in the ice bath for 30 minutes and then at ambient temperaturefor 1 hour. The reaction was filtered and the solids washed with MTBE(about 3 L). The filtrate was concentrated and the residue was purifiedby chromatography (3 kg silica, 7:1 to 3:1 Hex/EtOAc) to afford an oilthat slowly solidified under vacuum. The solids were ground using amortar and pestle, washed with hexanes (about 1000 mL) and dried toafford (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (158 g, 531 mmol, 73.8% yield) as a white solid.

Step K: A flask was charged with(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (2.32 g, 7.79 mmol), sodium thiocyanate (0.557 g, 6.87 mmol),pyridine (1.67 ml, 20.6 mmol), and acetonitrile (100 mL). The reactionwas heated to 40° C. for 30 minutes, then5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-amine(1.5 g, 4.58 mmol) was added and the reaction was heated to 70° C.overnight. Water was added and the reaction was extracted with ethylacetate and dichloromethane. The combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified over silica gel (50-100% ethyl acetate in hexanes) to afford(S)-N-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(1.38 g, 2.50 mmol, 54.6% yield) as yellow solid.

Step L: A flask was charged with(S)-N-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(1.38 g, 2.50 mmol), ethanol (50 mL), and 3M HCl (1.67 ml, 5.00 mmol)and heated to 75° C. for 1 hour. The reaction was cooled to ambienttemperature, and saturated aqueous sodium bicarbonate was added slowly.The mixture was extracted with ethyl acetate and dichloromethane. Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified over silica gel (50 to100% ethyl acetate in hexanes followed 5% methanol in ethyl acetate).The product was dissolved in 10% methanol in dichloromethane and 5 mL 2MHCl in ether was added. The solution was concentrated and dried in avacuum oven to afford(S)-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride (0.958 g, 1.65 mmol, 65.9% yield) as yellow solid. MassSpectrum (apci) m/z=472.1 (M+H—HCl).

Example 148(S)-1-(5-(5-(2-methoxyethylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride

Step A: A flask was charged with powdered potassium hydroxide (21.89 g,390.2 mmol), benzoic acid (47.65 g, 390.2 mmol), and DMF (500 mL) wasadded. The mixture was heated at 50° C. for 1 hour.3-Chloropentane-2,4-dione (52.5 g, 390.2 mmol) and the reaction wasstirred at 50° C. overnight. The reaction was cooled to ambienttemperature, diluted in water (1.5 L) and extracted with ether (3×500mL). The combined organic layers were washed with water, saturated NH₄Cland brine. The organic layer was dried over sodium sulfate andconcentrated in vacuo to afford 2,4-dioxopentan-3-yl benzoate (82.59 g,96.12% yield) as yellow oil.

Step B: A flask was charged with 2,4-dioxopentan-3-yl benzoate (82.59 g,375.0 mmol) and ethanol (1.5 L). To this solution was addedmethylhydrazine (39.90 ml, 750.1 mmol) in ethanol (150 mL). The reactionwas stirred at ambient temperature for 2 hours and concentrated in vacuoto afford 1,3,5-trimethyl-1H-pyrazol-4-yl benzoate (80 g, 92.6% yield).

Step C: A flask was charged with 1,3,5-trimethyl-1H-pyrazol-4-ylbenzoate (80 g, 347 mmol), and 500 mL ethanol. To the above mixture wasadded 3M NaOH (174 ml, 521 mmol) and stirred at ambient temperature for2 hours. The ethanol was removed in vacuo and the aqueous layer wasextracted with dichloromethane, ethyl acetate anddichloromethane:isopropyl alcohol (4:1). The combined organic layerswere dried over sodium sulfate, filtered and concentrated in vacuo toafford 1,3,5-trimethyl-1H-pyrazol-4-ol (34 g, 78% yield) as white solid.

Step D: A flask was charged with 1,3,5-trimethyl-1H-pyrazol-4-ol (10.46g, 82.89 mmol), and DMF:dioxane (9:1) (700 mL). The reaction mixture wascooled to 0° C. and 60% sodium hydride (3.315 g, 82.89 mmol) was addedportionwise. The reaction mixture was stirred for 15 minutes, then5-bromo-3-nitropicolinonitrile (18 g, 78.95 mmol) was added and thereaction was stirred at ambient temperature for 3 hours. The reactionwas poured slowly into 600 mL water and stirred for 10 minutes. Theresultant solids were filtered and dried to afford5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (23.70 g,97.74% yield) as very lightly tan (white) solid.

Step E: A flask was charged with5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (7.0 g, 23mmol) and H₂SO₄ (56 g, 570 mmol) and the reaction was stirred at ambienttemperature overnight. The reaction was cooled in an ice bath and water(100 mL) was carefully added. 40% NaOH solution was slowly added tillthe pH was about 12. The mixture was extracted with ethyl acetate anddichloromethane, and the combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo to afford5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinamide (7.4 g, 23mmol, 100% yield) as light yellow solid.

Step F: A flask was charged with 3M KOH (45.5 ml, 137 mmol) and bromine(1.98 ml, 38.7 mmol) and the reaction was stirred for 5 minutes atambient temperature.5-Bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinamide (7.4 g, 22.8mmol) in dioxane (150 mL) was added and the reaction was stirred atambient temperature for 6 hours. Water was added and the reaction wasextracted with ethyl acetate. The combined organic layers were driedover sodium sulfate, filtered and concentrated in vacuo. The residue waspurified over silica gel (50 to 100% ethyl acetate in hexanes) to afford5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-amine (3.8 g,12.8 mmol, 56.2% yield) as yellow solid.

Step G: To 1000 mL of DI water was added hydroxyl amine hydrochloride(51.0 g, 734 mmol) and the mixture was stirred for 5 minutes. Sodiumcarbonate (38.1 g, 360 mmol) was added in 3 large portions and thereaction was stirred for 15 minutes. THF (700 mL) was added, followed by(R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734 mmol) in 800 mLof THF. The reaction was stirred for 4 hours. The layers separated andthe aqueous layer was extracted twice with MTBE (about 3000 mL total).The combined organic layers were washed with water (700 ml) and brine(300 mL), dried over MgSO₄, and concentrated in vacuo to afford(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%) as aclear viscous oil.

Step H: To a 4-neck 2 L round bottom flask was added(S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135.1 g, 729.4 mmol)and 750 mL of DMF. The reaction was placed in a water bath and1-chloropyrrolidine-2,5-dione (97.40 g, 729.4 mmol) was added inportions over 2 minutes. The reaction was stirred in the water bath for3 hours, then diluted with 2 L of MTBE and washed with 1 L of water. Theaqueous layer was extracted with 500 mL of MTBE. The combined organiclayers were washed with water (5×800 mL) and brine (300 mL), dried overMgSO₄ and concentrated in vacuo to afford added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,98%) as a green viscous oil.

Step I: To a 4 neck 5 L flask was added(R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g,719 mmol) in 2.5 L of THF. The mixture was cooled to 3° C. andmethanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portionsover 10 minutes. N-ethyl-N-isopropylpropan-2-amine (126 ml, 719 mmol)was added through an addition funnel over 12 minutes. The reaction wasstirred in an ice bath for 30 minutes and then at ambient temperaturefor 1 hour. The reaction was filtered and the solids were washed withMTBE (about 3 L). The filtrate was concentrated and the residue waspurified by chromatography (3 kg silica, 7:1 to 3:1 Hexane/EtOAc) toafford an oil that slowly solidified under vacuum. The solids wereground using a mortar and pestle, washed with hexanes (about 1000 mL)and dried to afford(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (158 g, 531 mmol, 73.8% yield) as a white solid.

Step J: A flask was charged with(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoylchloride (1.53 g. 5.15 mmol), pyridine (1.25 ml, 15.4 mmol), sodiumthiocyanate (0.417 g, 5.15 mmol) and acetonitrile (15 mL). The solutionwas heated to 40° C. for 40 minutes.5-Bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-amine (1.02 g,3.43 mmol) was added and the reaction was heated to 70° C. overnight.The reaction was cooled to ambient temperature, partitioned betweenEtOAc and water, dried over sodium sulfate, filtered and concentrated.The residue was purified over silica gel (10% MeOH/EtOAc) to afford(S)-N-(5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(1.66 g, 3.18 mmol, 92.7% yield) as a yellow solid.

Step K: A sealed tube was charged with(S)-N-(5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.550 g, 1.055 mmol), Pd₂(dba)₃ (0.06065 g, 0.1055 mmol), K₃PO₄ (0.5821g, 2.742 mmol), Xantphos (0.1221 g, 0.2110 mmol), and degassed toluene(5 mL). Nitrogen was bubbled through the solution for 5 minutes. Methyl3-mercaptopropanoate (0.1752 ml, 1.582 mmol) was added and the reactionwas heated to 100° C. overnight. The reaction was cooled to ambienttemperature, water was added and the reaction was extracted with ethylacetate. The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified over silica gel (50 to100% ethyl acetate in hexanes) to afford (S)-methyl3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-3-ylthio)propanoate(0.276 g, 0.4923 mmol, 46.67% yield) as yellow oil.

Step L: To a solution of (S)-methyl3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-3-ylthio)propanoate(0.420 g, 0.749 mmol) in THF (10 mL) was added potassium2-methylpropan-2-olate (2.36 ml, 2.36 mmol) and the reaction was stirredat ambient temperature for 5 minutes. 1-Bromo-2-methoxyethane (0.132 g,0.899 mmol) (as a solution in 2 mL THF) and DMF (1 mL) were added andthe reaction was stirred for 20 minutes at ambient temperature. Thesolution was quenched with water, extracted with CH₂Cl₂, dried oversodium sulfate, filtered and concentrated. The residue was purified oversilica gel (100% EtOAc) to afford(S)-N-(5-(2-methoxyethylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.200 g, 50.1% yield).

Step M: A flask was charged with(S)-N-(5-(2-methoxyethylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine(0.200 g, 0.375 mmol), 3M HCl (0.751 ml, 0.751 mmol), and ethanol (5mL). The reaction was heated to 80° C. for 1 hour and then cooled toambient temperature. The reaction was concentrated in vacuo and purifiedusing reverse phase chromatography (5 to 95% acetonitrile in water) toafford(S)-1-(5-(5-(2-methoxyethylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diolhydrochloride (0.165 g, 0.298 mmol, 79.4% yield) as white solid afterHCl salt formation. Mass Spectrum (apci) m/z=453.1 (M+H—HCl).

Example 149(R)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol

Step A: To a solution of (S)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanone(10.5 g, 72.8 mmol) in 150 (mL) THF: 60 mL was added hydroxylaminehydrochloride (5.06 g, 72.8 mmol), and the reaction was stirred for 20minutes. Na₂CO₃ (3.78 g, 35.7 mmol) was added and the reaction wasstirred overnight. The reaction was extracted with ethyl acetate, washedwith water and brine, dried over MgSO₄, filtered and concentrated toafford (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde oxime (10.3 g, 71.0mmol, 97.4% yield).

Step B: To a solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehydeoxime (10.3 g, 71.0 mmol) in 40 mL DMF was added1-chloropyrrolidine-2,5-dione (10.4 g, 78.1 mmol) and the reaction wasstirred overnight at ambient temperature. The reaction mixture waspoured into ether (1400 mL) and water (500 mL). The ether layer wasextracted with water (5×500 mL), dried over MgSO₄, filtered andconcentrated to (S)-N-hydroxy-2,2-dimethyl-1,3-dioxolane-4-carbimidoylchloride (10.0 g, 55.7 mmol, 78.5% yield) as white solid.

Step C: A solution of(S)-N-hydroxy-2,2-dimethyl-1,3-dioxolane-4-carbimidoyl chloride (9.88 g,55.01 mmol) in THF (200 mL) at 0° C. was added methanesulfonyl chloride(4.703 ml, 60.51 mmol), followed by N,N-diisopropylethylamine (10.54 ml,60.51 mmol) and the reaction was stirred for 1 hour at ambienttemperature, filtered and concentrated in vacuo. The residue waspurified over silica gel (25 to 100% ethyl acetate in hexanes) to afford(S)-2,2-dimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoylchloride (12.28 g, 47.65 mmol, 86.63% yield) as colorless oil.

Step D: To 600 mL of DMF in a 4 neck 3000 mL round bottom flask equippedwith an overhead stir mechanism under nitrogen was added2-methylpyridin-3-ol (71.8 g, 658 mmol) and the mixture was cooled to 2°C. 60% Sodium hydride (26.3 g, 658 mmol) was added over 30 minutes whilemaintaining the internal temperature below 10° C. The reaction wasstirred while warming to ambient temperature for 1 hour.5-Bromo-3-nitropicolinonitrile (150 g, 658 mmol) in a solution of 400 mLof DMF was added in two portions and the reaction was held at ambienttemperature for 1.5 hours. Pyridine-2-thiol (73.1 g, 658 mmol) was addedas a solid in portions and the reaction was stirred for 15 minutes todissolved the material, then cooled to 3° C. Sodium hydride (26.3 g, 658mmol) was added in portions over 35 minutes while maintaining theinternal temperature below 10° C. The reaction was removed from the icebath and warmed to ambient temperature while stirring for 12 hours. Thereaction was diluted with 4 volumes (8 L) of brine and stirred for 30minutes, at which point solid formed. The solid was filtered off andfiltrate extracted with MTBE (10 L total). The MTBE phase wasconcentrated in vacuo. The solid was combined with concentrated materialand dissolved in ethyl acetate (3 L). The organic layer was washed withbrine (4×1 L), dried over MgSO₄, filtered and concentrated in vacuo. Thesolid that formed was ground into a powder and dried in vacuo for 4hours. The powder was taken up in 30 mL of MTBE/10 g of product and themixture was stirred for 30 minutes. The solid was filtered and dried invacuo (2 hours). The mother liquor was concentrated and triturated withMTBE (same diluted rate). The solids were combined and dried for 3 hoursin vacuo to yield3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (181 g,85%).

Step E: To concentrated H₂SO₄ (90 mL) cooled with an ice bath was added3-2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (43 g,130 mmol) in portions such that the internal temp did not exceed 50° C.but did not go below 25° C. After complete addition, the mixture wasstirred in the ice bath until the reaction started to cool, at whichpoint the reaction was removed from the ice bath and the mixture washeated to 50° C. The reaction was cooled to ambient temperature and themixture added to ice water slowly over 3 minutes (about 1400 mL of 30%ice in water). The mixture was further cooled in an ice bath to 5° C.The mixture was neutralized to about pH with 4M NaOH (about 800 mL)while maintaining the internal temperature below 20° C., at which pointa solid formed. The mixture was stirred for 20 minutes. The mixture wasfiltered and washed with MTBE (5×150 mL), hexanes (5×100 mL), and driedat under vacuum to afford3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (43 g,96%).

Step F: To a solution of NaOH (2M, 90 mL, 182 mmol) at 0° C. was addedbromine (8.71 g, 54 mmol) and the reaction was stirred at 0° C. for 30minutes. 5-Bromo-3-(2-methylpyridin-3-yloxy)picolinamide (11.2 g, 36.3mmol) in dioxanes (100 mL) was added and the reaction was stirred atambient temperature for 1 hour, followed by heating to 80° C. for 1hour. The reaction was cooled to ambient temperature and acidified to pH1 using concentrated HCl. The reaction was basified and a solidprecipitated. The solid was filtered and dried in vacuo to yield5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (4.1 g, 41%).

Step G: A flask was charged with(S)-2,2-dimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoylchloride (4.5 g, 18 mmol), sodium thiocyanate (1.3 g, 15 mmol), pyridine(3.8 ml, 46 mmol), and ethyl acetate (200 mL). The reaction was stirredand heated at 40° C. for 45 minutes.3-(2-Methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (3.2 g,10 mmol) was added and the reaction was stirred at 70° C. overnight.Water was added and the reaction was extracted with ethyl acetate, driedover sodium sulfate, filtered and concentrated. The residue was purifiedover silica gel (25 to 100% ethyl acetate in hexanes) to afford(R)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(3.8 g, 7.7 mmol, 75% yield).

Step H: A flask was charged with(R)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(3.8 g, 7.683 mmol) and added ethanol (40 mL). 3M HCl (5.122 ml, 15.37mmol) was added, and the reaction was heated to 70° C. for 1 hour, thencooled to ambient temperature. The ethanol removed in vacuo andsaturated sodium bicarbonate solution was added. The aqueous layer wasextracted with ethyl acetate. The majority of product crashed out of theaqueous layer and collected by filtration. The solids and residue fromorganic layer were purified over silica gel (10-15% methanol in ethylacetate) to afford(R)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-4-yl)ethane-1,2-diol(2.877 g, 6.330 mmol, 82.38% yield) as yellow solid. Mass Spectrum(apci) m/z=455.1 (M+H).

Example 150(S)-2-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diolhydrochloride

Step A: To 600 mL of DMF in a 4 neck 3000 mL round bottom flask equippedwith an overhead stir mechanism under nitrogen was added2-methylpyridin-3-ol (71.8 g, 658 mmol) and the reaction was cooled to2° C. Sodium hydride (60%; 26.3 g, 658 mmol) was added over a period of30 minutes at a rate such that the internal temperature did not exceed10° C. The reaction was stirred while warming to ambient temperature for1 hour. 5-Bromo-3-nitropicolinonitrile (150 g, 658 mmol) in a solutionof 400 mL of DMF was added in two portions and the reaction was held atambient temperature for 1.5 hour. To the reaction at ambient temperaturewas added pyridine-2-thiol (73.1 g, 658 mmol) as a solid in portions andthe reaction was stirred for 15 minutes to dissolve the material. Thereaction was cooled to 3° C. and sodium hydride (26.3 g, 658 mmol) wasadded in portions over 35 minutes at a rate such that the internaltemperature did not go above 10° C. The reaction was removed from theice bath and warmed to ambient temperature while stirring for 12 hour.The reaction was diluted with 4 volumes (8 L) of brine and stirred for30 minutes, at which point solid formed. The solid was filtered off andthe filtrate was extracted with MTBE (10 L total). The MTBE phase wasconcentrated in vacuo. The solid was combined with concentrated materialand dissolved in ethyl acetate (3 L). The EtOAc was washed with brine(4×1 L), dried over MgSO₄, filtered and concentrated in vacuo. The solidthat formed was ground into a powder and dried in vacuo for 4 hours. Thepowder was taken up in 30 mL of MTBE/10 g of product and the mixture wasstirred for 30 minutes. The solid was filtered and dried in vacuo (2hours). The mother liquor was concentrated and triturated with MTBE(same dilution rate). The solids were combined and dried for 3 hours invacuo to yield3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (181 g,85%)

Step B: To concentrated H₂SO₄ (90 mL) cooled with an ice bath was added3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (43 g,130 mmol) in portions such that the internal temperature did not exceed50° C. but did not go below 25° C. After complete addition, the mixturewas stirred in the ice bath until the reaction started to cool, at whichpoint the reaction was removed from the ice bath and the mixture washeated to 50° C. The reaction was cooled to ambient temperature and thenadded to ice water slowly over 3 minutes (about 1400 mL of 30% ice inwater). The mixture was further cooled in an ice bath to 5° C. andneutralized to about pH 10 with 4M NaOH (about 800 mL) while maintainingthe internal temperature below 20° C., at which point a solid formed.The mixture was stirred for 20 minutes, then filtered and washed withMTBE (5×150 mL) and hexanes (5×100 mL), and dried at under vacuum toafford (3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (43g, 96%).

Step C: To a 3-neck 2 L round bottom flask was added 2M aqueous sodiumhydroxide (343 ml, 686 mmol) and the solution was cooled in an ice bath.Bromine (12 ml, 257 mmol) was added and the reaction was stirred for 30minutes while the ice bath was removed.3-(2-Methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (58 g, 171mmol) was added as a slurry in about 600 mL of dioxanes in 1 portion.After 30 minutes, concentrated HCl was added in 1 mL portions to adjustthe mixture to about pH 1. The reaction was stirred for 15 minutes and4N NaOH was added to the solution to about pH 10. The aqueous mixturewas extracted with EtOAc (3×750 mL), washed with water (2×250 mL) andbrine (300 mL), dried over MgSO₄, filtered and concentrated. Thematerial was dried in vacuo at 50° C. at which point a red solid formed.The solid was triturated with CH₂Cl₂ and dried under vacuum at 50° C.The filtrate was concentrated in vacuo and material purified over silicagel (3% MeOH/CH₂Cl₂) to afford a red solid. The two crops were combinedto afford3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (24 g,45%).

Step D: O,N-dimethylhydroxylamine hydrochloride (74.6 g, 765 mmol) wasdissolved in THF (1 L) and pyridine (123 ml, 1531 mmol) was added andstirred for 30 minutes. Methacryloyl chloride (37.4 ml, 383 mmol) wasadded slowly and stirred overnight. The solids were filtered andconcentrated. The residue was partitioned between water and CH₂Cl₂,washed with water, dried over sodium sulfate, filtered and concentratedto afford N-methoxy-N-methylmethacrylamide (56.5 g, 335 mmol, 87.5%yield).

Step E: A round bottom flask was charged with t-BuOH (850 mL), water(850 mL), Ad-Mix-α (230 g, 166 mmol) and methanesulfonamide (15.8 g, 166mmol). The mixture was stirred at ambient temperature until both phaseswere clear (about 5 minutes) and then cooled to 0° C., after whichorange salts precipitated. N-methoxy-N-methylmethacrylamide (21.5 g, 166mmol) was added and the heterogeneous slurry was stirred vigorously at0° C. for 2 hours, warmed to ambient temperature and stirred for 24hours. The reaction was quenched by the slow, portionwise addition ofsodium bisulfite (223 g) and stirred for 1 hour. The reaction mixturewas extracted with EtOAc (3×300 mL), dried over sodium sulfate, filteredand concentrated to afford(R)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32.7 g, 200 mmol,120% yield) as a yellow oil.

Step F: (R)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32 g, 196mmol) was dissolved in 2,2-dimethoxypropane (241 ml, 1961 mmol) and4-methylbenzenesulfonic acid hydrate (3.73 g, 19.6 mmol) was added andstirred at ambient temperature overnight. The reaction was partitionedbetween saturated aqueous sodium bicarbonate and CH₂Cl₂, extracted withCH₂Cl₂, dried over sodium sulfate, filtered and concentrated to afford(R)-N-methoxy-N,2,2,4-tetramethyl-tetramethyl-1,3-dioxolane-4-carboxamide(22.9 g, 113 mmol, 57.5% yield).

Step G: (R)-N-methoxy-N,2,2,4-tetramethyl-1,3-dioxolane-4-carboxamide(22.9 g, 113 mmol) was dissolved in THF (500 mL) and cooled to −78° C.1M LAH (124 ml, 124 mmol) was added slowly through an addition funnelover about 30 minutes. The reaction was stirred for another 30 minutes,a saturated aqueous NH₄Cl was added (125 mL) and the reaction wasallowed to warm to ambient temperature. After filtration, the slurrymixture was washed several times with EtOAc, and concentrated to affordcrude (R)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde (10 g, 69.4 mmol,61.6% yield) which was taken on to next reaction without furtherpurification.

Step H: (R)-2,2,4-Trimethyl-1,3-dioxolane-4-carbaldehyde (6.9 g, 48mmol) was dissolved in 1:1 methanol water (100 mL), and hydroxylaminehydrochloride (3.3 g, 48 mmol) and Na₂CO₃ (2.5 g, 24 mmol) were added.The reaction was stirred at ambient temperature overnight. The methanolwas removed in vacuo and the remaining material was extracted withCH₂Cl₂, dried over sodium sulfate, filtered and concentrated to afford(S)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde oxime (5.7 g, 36 mmol,75% yield).

Step I: (S)-2,2,4-Trimethyl-1,3-dioxolane-4-carbaldehyde oxime (5.7 g,36 mmol) was dissolved in DMF (120 mL) and 1-chloropyrrolidine-2,5-dione(4.8 g, 36 mmol) was added. The reaction was stirred at ambienttemperature overnight, and then poured in water (600 mL) with stirring.After 15 minutes the cloudy suspension was extracted with EtOAc, washedwith water and brine, dried over sodium sulfate, filtered andconcentrated to afford(R)-N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoyl chloride (6.4g, 33 mmol, 92% yield).

Step J: (R)-N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoylchloride (6.4 g, 33.1 mmol) was dissolved in Et₂O (150 mL) andmethanesulfonyl chloride (2.21 ml, 28.4 mmol) was added. Triethylamine(3.96 ml, 28.4 mmol) was added dropwise and the reaction stirred atambient temperature for 1 hour. The resulting solids were filtered andthe filtrate was concentrated. The residue was purified over silica gel(100% CH₂Cl₂) to afford(R)-2,2,4-trimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoylchloride (5.8 g, 21.3 mmol, 64.6% yield) as an amber oil.

Step K:(R)-2,2,4-trimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoylchloride (350 mg, 1.29 mmol) was dissolved in CH₃CN (6 mL). NaNCS (104mg, 1.29 mmol) and pyridine (260 μl, 3.22 mmol) were added and thereaction was heated to 45° C. for 45 minutes.3-(2-Methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (200 mg,0.644 mmol) was added and the reaction was heated to 70° C. for 24hours. The reaction was poured into water and extracted with EtOAc,dried over sodium sulfate, filtered and concentrated. The residue waspurified over silica gel (80% EtOAc in hexanes) to afford(S)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine(55 mg, 0.108 mmol, 16.8% yield).

Step L:(S)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine(55 mg, 0.108 mmol) was dissolved in EtOH (3 mL). 1M HCl (0.3 mL) wasadded and the mixture was stirred at ambient temperature for 24 hours.Additional 1M HCl (0.3 mL) was added and the mixture was stirredovernight. The mixture was partitioned between saturated aqueous sodiumbicarbonate and CH₂Cl₂, dried over sodium sulfate, filtered andconcentrated. The residue was purified over silica gel (15% methanol inEtOAc) to afford(S)-2-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diolhydrochloride (34.9 mg, 0.0691 mmol, 63.9% yield) as a white solid afterHCl salt formation. Mass Spectrum (apci) m/Z=451.1 (M+H—H₂O—HCl) (100)and 469.1 (M+H—HCl) (30).

Example 151(R)-2-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino-1,2,4-thiadiazol-3-yl)propane-1,2-diolhydrochloride

Step A: To 600 mL of DMF in a 4 neck 3000 mL round bottom flask equippedwith an overhead stir mechanism under nitrogen was added2-methylpyridin-3-ol (71.8 g, 658 mmol) and the reaction was cooled to2° C. Sodium hydride (60%; 26.3 g, 658 mmol) was added over a period of30 minutes at a rate such that the internal temperature did not exceed10° C. the reaction was stirred while warming to ambient temperature for1 hour. 5-Bromo-3-nitropicolinonitrile (150 g, 658 mmol) in a solutionof 400 mL of DMF was added in two portions and the reaction held atambient temperature for 1.5 hour. To the reaction at ambient temperaturewas added pyridine-2-thiol (73.1 g, 658 mmol) as a solid in portions andthe reaction was stirred for 15 minutes to dissolve the material. Thereaction was cooled to 3° C. and sodium hydride (26.3 g, 658 mmol) againwas added in portions over 35 minutes such that the internal temperaturedid not go above 10° C. The reaction was removed from the ice bath andwarmed to ambient temperature while stirring for 12 hours. The reactionwas diluted with 4 volumes (8 L) of brine and stirred for 30 minutes, atwhich point solid formed. The solid was filtered off and the filtratewas extracted with MTBE (10 L total). The MTBE phase was concentrated invacuo. The solid was combined with concentrated material and dissolvedin ethyl acetate (3 L). The EtOAc was washed with brine (4×1 L), driedover MgSO₄, filtered and concentrated in vacuo. The solid that formedwas ground into a powder and dried in vacuo for 4 hours. The materialwas taken up in 30 mL of MTBE/10 g of product and the reaction wasstirred for 30 minutes. The solid was filtered and dried in vacuo (2hours). The mother liquor was concentrated and triturated with MTBE(same dilution rate). The solids were combined and dried for 3 hours invacuo to yield3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (181 g,85%).

Step B: To concentrated H₂SO₄ (90 mL) cooled with an ice bath was added3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (43 g,130 mmol) in portions such that the internal temperature did not exceed50° C. but did not go below 25° C. After complete addition, the mixturewas stirred in the ice bath until the reaction started to cool, at whichpoint the reaction was removed from the ice bath and the mixture washeated to 50° C. The reaction was cooled to ambient temperature andadded to ice water slowly over 3 minutes (about 1400 mL of 30% ice inwater). The mixture was further cooled in an ice bath to 5° C. andneutralized to about pH 10 with 4M NaOH (about 800 mL) at a rate suchthat the internal temperature did not exceed 20° C., at which point asolid formed. The mixture was stirred for 20 minutes, then filtered andwashed with MTBE (5×150 mL), hexanes (5×100 mL), and dried at undervacuum to afford3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (43 g,96%).

Step C: To a 3-neck 2 L round bottom flask was added 2M aqueous sodiumhydroxide (343 ml, 686 mmol) and the solution was cooled in an ice bath.Bromine (12 ml, 257 mmol) was added and the reaction was stirred for 30minutes while the ice bath was removed.3-(2-Methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (58 g, 171mmol) was added as a slurry in about 600 mL of dioxanes in 1 portion.After 30 minutes, concentrated HCl was added in 1 mL portions to aboutpH 1. The reaction was stirred for 15 minutes and 4N NaOH was added tothe solution to pH ˜10. The aqueous mixture was extracted with EtOAc(3×750 mL), washed with water (2×250 mL) and brine (300 mL), dried overMgSO₄, filtered and concentrated. The material was dried in vacuo at 50°C. at which point a red solid formed. The solid was triturated withCH₂Cl₂ (about 40 mL of CH₂Cl₂ to 5 g of material) and the solidfiltered. The solid was washed with CH₂Cl₂ and dried under vacuum at 50°C. the filtrate was concentrated in vacuo and the residue was purifiedover silica gel (3% MeOH/CH₂Cl₂) to afford a red solid. The two cropswere combined to afford3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (24 g,45%).

Step D: O,N-dimethylhydroxylamine hydrochloride (74.6 g, 765 mmol) wasdissolved in THF (1 L) and pyridine (123 ml, 1531 mmol) was added andstirred for 30 min. Methacryloyl chloride (37.4 ml, 383 mmol) was addedslowly and stirred overnight. The solids were filtered and concentrated.The residue was partitioned between water and CH₂Cl₂, washed with water,dried over sodium sulfate, filtered and concentrated to affordN-methoxy-N-methylmethacrylamide (56.5 g, 335 mmol, 87.5% yield).

Step E: A round bottom flask was charged with ³BuOH (850 mL), water (850mL), Ad-Mix-β (230 g, 166 mmol) and methanesulfonamide (15.8 g, 166mmol). The mixture was stirred at ambient temperature until both phaseswere clear (about 5 minutes) and then cooled to 0° C., after whichorange salts precipitated. N-methoxy-N-methylmethacrylamide (21.5 g, 166mmol) was added and the heterogeneous slurry was stirred vigorously at0° C. for 2 hours and warmed to ambient temperature and stirred for 24hours. The reaction was quenched by the slow, portionwise addition ofsodium bisulfite (223 g) and stirred for 1 hour. The reaction mixturewas extracted with EtOAc (3×300 mL), dried over sodium sulfate, filteredand concentrated to afford(S)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32 g, 196 mmol,118% yield) as a yellow oil.

Step F: (S)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32 g, 196mmol) was dissolved in 2,2-dimethoxypropane (241 ml, 1961 mmol,4-methylbenzenesulfonic acid hydrate (3.73 g, 19.6 mmol) was added, andthe reaction was stirred at ambient temperature overnight. The reactionwas partitioned between CH₂Cl₂ and saturated aqueous sodium bicarbonate,extracted with CH₂Cl₂, dried over sodium sulfate, filtered andconcentrated. The residue was purified on silica plug (1.5 L, elutingwith 25% EtOAc in hexanes) to afford(S)-N-methoxy-N,2,2,4-tetramethyl-1,3-dioxolane-4-carboxamide (23.1 g,114 mmol, 58.0% yield).

Step G: (S)-N-methoxy-N,2,2,4-tetramethyl-1,3-dioxolane-4-carboxamide(23.1 g, 114 mmol) was dissolved in THF (600 mL) and cooled to −78° C.DIBAL-H (1M in toluene, 125 ml, 125 mmol) was added slowly through anaddition funnel over about 15 minutes. The reaction was stirred for anadditional 30 minutes at −78° C. and then quenched with saturatedaqueous NH₄Cl. The mixture was partitioned between EtOAc and water. Thetwo layers were filtered through a silica plug and separated. Theorganic layer was dried over sodium sulfate, filtered and concentratedto afford (S)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde (16.4 g, 114mmol, 100% yield).

Step H: (S)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde (5.8 g, 40mmol) was dissolved in 1:1 methanol water (100 mL) and hydroxylaminehydrochloride (2.8 g, 40 mmol) and Na₂CO₃ (2.1 g, 20 mmol). The reactionwas stirred at ambient temperature overnight, then concentrated invacuo. The aqueous layer was extracted with CH₂Cl₂, and the organiclayer was dried over sodium sulfate, filtered and concentrated to afford(R)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde oxime (4.8 g, 30 mmol,75% yield).

Step I: (R)-2,2,4-Trimethyl-1,3-dioxolane-4-carbaldehyde oxime (4.8 g,30 mmol) was dissolved in DMF (100 mL) and 1-chloropyrrolidine-2,5-dione(4.0 g, 30 mmol) was added. The reaction was stirred at ambienttemperature overnight, then poured in water (600 mL) with of stirring.After 15 minutes the cloudy suspension was extracted with EtOAc andwashed with water and brine. The organic layer was dried over sodiumsulfate, filtered and concentrated to afford(S)-N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoyl chloride (5.5g, 28 mmol, 94% yield).

Step J: (S)-N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoylchloride (5.5 g, 28.4 mmol) was dissolved in Et₂O (150 mL) andmethanesulfonyl chloride (2.21 ml, 28.4 mmol) was added. Triethylamine(3.96 ml, 28.4 mmol) was added dropwise and the reaction was stirred atambient temperature for 1 hour. The resulting solids were filtered andthe filtrate concentrated. The residue was purified over silica gel(100% CH₂Cl₂) to afford(S)-2,2,4-trimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoylchloride (4.7 g, 17.3 mmol, 60.9% yield) as an amber oil.

Step K:(S)-2,2,4-Trimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoylchloride (438 mg, 1.61 mmol) was dissolved in CH₃CN (6 mL) and NaNCS(131 mg, 1.61 mmol) and pyridine (311 μL, 3.87 mmol) were added and thereaction was heated to 45° C. for 45 minutes.3-(2-Methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (200 mg,0.644 mmol) was added and the reaction was heated to 70° C. for 24hours. The reaction was poured into water and extracted with EtOAc,dried over sodium sulfate, filtered and concentrated. The residue waspurified over silica gel (80% EtOAc in hexanes) to afford(R)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine(65 mg, 0.128 mmol, 19.8% yield).

Step L:(R)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine(65 mg, 0.128 mmol) was dissolved in EtOH (3 mL) and 1M HCl (0.3 mL) wasadded. The mixture was stirred at ambient temperature for 24 hours.Additional 1M HCl (0.3 mL) was added and the mixture was stirredovernight. The mixture was partitioned between saturated aqueous sodiumbicarbonate and CH₂Cl₂, and the organic layer was dried over sodiumsulfate, filtered and concentrated. The residue was purified over silicagel (15% methanol in EtOAc) to afford(R)-2-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diolhydrochloride (42.6 mg, 0.0844 mmol, 66.0% yield) as a white solid afterHCl salt formation. Mass Spectrum (apci) m/z=469.1 (M+H—HCl).

Example A In Vitro Glucokinase Assays

The in vitro efficacy of glucokinase activators of the present inventionwas assessed in two separate assays: an EC₅₀ assay to evaluate thepotency of each compound at a fixed, physiologically relevantconcentration of glucose, and a glucose S_(0.5) assay at a fixed, nearsaturating (if possible) concentration of compound to evaluate itseffect on the V_(m) and S_(0.5) for glucose. For each of these assays,glucokinase activity was estimated by monitoring the increase inabsorbance at 340 nm in a coupled assay system containing NAD+ andglucose 6-phosphate dehydrogenase. Assays were conducted at 30° C. usinga thermostatically controlled absorbance plate reader (Spectramax 340PC,Molecular Devices Corp.) and clear, 96-well, flat bottom polystyreneplates (Costar 3695, Corning). Each 50-μL assay mixture contained 10 mMK+MOPS, pH 7.2, 2 mM MgCl₂, 50 mM KCl, 0.01% Triton X-100, 2% DMSO, 1 mMDTT, 1 mM ATP, 1 mM NAD+, 5 U/mL glucose 6-phosphate dehydrogenase,approximately 5 or 0.2 nM human glucokinase and (depending on the assay)varying concentrations of glucose and test compound. The absorbance at340 nm was monitored kinetically over a period of 5 minutes (10s/cycle), and rate were estimated from the slopes of linear fits to theraw data.

Glucokinase EC₅₀ Assay:

For this assay, the glucose concentration was fixed at 5 mM, while thecontrol or test compound was varied over a 10-point, 3-fold dilutionseries and typically ranged from a high dose of 50 μM to a low dose ofapproximately 2.5 nM. In certain assays, the plasma protein bindingpotential of each of the test compounds was assessed by the inclusion of4% human serum albumin (HSA) in the assay buffer and comparing theestimated EC₅₀ value with that determined in the absence of HSA.

In each case (with or without HAS), a standard, four-parameter logisticmodel (Equation 1) was fit to the raw data (rate versus concentration ofcompound):

$\begin{matrix}{y = {A + \frac{B - A}{1 + \left\lbrack \frac{C}{x} \right\rbrack^{D}}}} & (1)\end{matrix}$

where x is the concentration of compound, y is the estimated rate, A andB are the lower and upper asymptotes, respectively, C is the EC₅₀ and Dis the Hill slope. The EC₅₀ is defined as the midpoint or inflectionpoint between the upper and lower asymptotes.

The compounds exemplified herein have been found to have an EC₅₀ in therange of 6 and 50,000 nM in the above described assay. Certain compoundsexemplified herein have been found to have an EC₅₀ in the range of 2 and5000 nM. Certain compound exemplified herein were found to have an EC₅₀in the range of 10-400 when the assay was performed without HSA. Certaincompound exemplified herein were found to have an EC₅₀ in the range of30-1000 when the assay was performed with 4% HSA.

Glucose S_(0.5) Assay:

For this assay, the concentration of control or test compound was fixedat or near a saturating concentration, if possible, typically 50 μM,while the glucose concentration was varied over a 10-point, 2-folddilution series ranging from 80 to approximately 0.16 mM. The samefour-parameter logistic model used for the EC₅₀ assay (Equation 1) wasemployed to estimate the relevant kinetic parameters. In this assay, thedefinitions for the variables and parameters are similar except that xrepresents the concentration of glucose, B is the rate at saturatingglucose (V_(m)), C is the S_(0.5) for glucose (the concentration ofglucose at V_(m)/2) and D is the Hill Coefficient.

Certain compounds exemplified herein have been found to have an S_(0.5)of between 0.3 and 5 mM in the above described assay. Certain compoundsexemplified herein have been found to have an S_(0.5) of between 0.30and 1.5 mM.

Example B Mouse PK Study

Oral pharmacokinetics of each of the compounds shown in Table 1 (“testcompound”) were determined as follows.

Materials

Test compound was formulated in PEG400:ethanol:saline (40:20:40, byvolume) for IV administration and in 30% Captisol in water for both IVand PO administration in CD-1 mice. Labetalol was used as an internalstandard for the LC-MS/MS assay of the CD-1 mouse samples.

Adult male CD-1 mice were obtained from Charles River Laboratories inPortage, Mich. At the time of study-start, each CD-1 mouse weighedapproximately 30 grams and was between the ages of 7-9 weeks. All CD-1mice were acclimated to the Array BioPharma Inc. vivarium for at least 5days prior to administration of an IV dose by way of a tail veininjection (5 mL/kg) or a PO dose by oral gavage (10 mL/kg).

Animals were euthanized by CO₂ inhalation and blood samples werecollected by cardiac puncture into syringes containing a 1.5% EDTAsolution in water (w/v; pH was titrated to 7.4 with 5 N NaOH; the finalratio of blood to EDTA was approximately 1:9) as the anticoagulant.Plasma was harvested from blood samples by centrifugation and stored at−20° C. until analysis. The following time points were collected for theIV arm: 0.017, 0.083, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose.The following time points were collected for the PO arm: 0.25, 0.50, 1,4, 8, and 24 hours post dose.

Methods

Protein was precipitated from 20 μL of mouse plasma with the addition of200 μL of 0.1% acetic acid in acetonitrile. A single 12-pointcalibration curve was prepared by first serially diluting (3-fold) a40-μg/mL stock solution of the test compound in acetonitrile. Naïve CD-1mouse plasma (20 μL) was then added to each standard solution (200 μL).A stock solution of the internal standard (Labetalol; 180 μL of 0.1μg/mL in acetonitrile) was subsequently added to each standard andsample solution, for a total volume of 400 μL. Samples were vortex-mixedfor 5 minutes and spun in an Allegra X-12R centrifuge (Beckman Coulter,Fullerton, Calif.) for 15 minutes at approximately 1,500×g at 4° C. A100-μL aliquot of each supernatant was transferred via a 550 μL PersonalPipettor (Apricot Designs, Monrovia, Calif.) to 96-well plates anddiluted 1:1 with HPLC grade water. The resulting plates were sealed withplate mats and analyzed by LC-MS/MS.

The LC-MS/MS system was comprised of an HTC-PAL autosampler (LeapTechnologies, Inc., Carrboro, N.C.), an HP1100 HPLC (AgilentTechnologies Inc., Santa Clear, Calif.), and an API4000 triplequadrupole mass spectrometer (Applied Biosystems, Foster City, Calif.).Chromatographic retention of the analyte and internal standard wasachieved using a Betasil Phenyl-Hexyl column (2.1×30 mm, 3 μm particlesize, Thermo Scientific) in conjunction with gradient conditions usingmobile phases A (aqueous 0.1% formic acid and 1% IPA) and B (0.1% formicacid in acetonitrile). The total run time, including re-equilibrationtime, for a single injection was 3.5 minutes. Mass spectrometricdetection of the analytes was accomplished using ESI+ ionization mode.Ion current was optimized during infusion of a stock solution of thetest compound. Analyte responses were measured by multiple reactionmonitoring (MRM) of transitions unique to each compound.

Calculations

Data were acquired and processed using the Applied Biosystems Analystsoftware (version 1.4.2). Calibration was achieved by plotting the peakarea ratios of analyte to internal standard as a function of the nominalconcentrations of standard samples. A calibration model was generated byquadratic regression of the calibration curve with a weighting factor of1/x. The model was used to calculate the concentrations in all samples.The lower limit of quantitation (LLOQ) for this analysis was in thesingle-digit μg/mL range (either 2.03 or 6.10 μg/mL).

Pharmacokinetic parameters were calculated by establishednon-compartmental methods using an in-house Excel® (MicrosoftCorporation, Redmond, Wash.) macro, PK Toolbox version 2.0. Plasmaconcentrations of test compound from replicate animals (n=3) for eachtime-point were averaged. The average concentrations versus time weremodeled to determine PK parameters. Standard deviations of plasmaconcentrations were determined only when more than two replicates wereavailable for comparison (i.e., values greater than the LLOQ). The areaunder the plasma concentration versus time curve (AUC) was determinedusing linear trapezoidal integration. The portion of the AUC from thelast measurable concentration to infinity was estimated from theequation, C_(t)/k_(el), where C_(t) represents the last measurableconcentration and k_(el) is the elimination rate constant. The latterwas determined from the concentration versus time curve by linearregression of user-selected data points at the terminal phase of thesemi-logarithmic plot. Use sum of the AUC values before and afterextrapolation from the last time point is reported as the AUC_(inf)value. Oral bioavailability was calculated by taking the ratio of theaverage dose-normalized AUC_(inf) values for IV and PO administration.

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be considered to fall within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

1. A compound selected from:(S)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;(S)-2-methyl-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol;(S)-2-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol;(R)-2-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol;(S)-1-(5-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;(S)-1-(5-(3-(1-Ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;(S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-2-methylpropane-1,2-diol;(S)-2-methyl-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol;or pharmaceutically acceptable salts thereof.
 2. A compound selectedfrom(S)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol,or a pharmaceutically acceptable salt thereof.
 3. A compound selectedfrom(S)-2-methyl-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol,or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition, which comprises a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.
 5. The pharmaceutical composition ofclaim 4 wherein the compound is(S)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol,or a pharmaceutically acceptable salt thereof.
 6. The pharmaceuticalcomposition of claim 4 wherein the compound is(S)-2-methyl-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol,or a pharmaceutically acceptable salt thereof.
 7. A method of treatingnon-insulin-dependent diabetes comprising administering to a mammal atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 8. The method of claim 7wherein the compound is(S)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol,or a pharmaceutically acceptable salt thereof.
 9. The method of claim 7wherein the compound is(S)-2-methyl-1-(S-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol,or a pharmaceutically acceptable salt thereof.